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igf signaling
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Pituitary-derived growth hormone (GH) stimulates the liver to express IGF1, which is secreted and affects growth of multiple cell types (>>1<<, 2). Other tissues also produce IGF ligands that act in a paracrine or autocrine manner (3). IGF ligands are bound by insulin-like growth factor binding proteins (IGFBP1-6) (4). While IGFBP binding increases ligand stability, IGFBP
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Pituitary-derived growth hormone (GH) stimulates the liver to express IGF1, which is secreted and affects growth of multiple cell types (1, >>2<<). Other tissues also produce IGF ligands that act in a paracrine or autocrine manner (3). IGF ligands are bound by insulin-like growth factor binding proteins (IGFBP1-6) (4). While IGFBP binding increases ligand stability, IGFBP binding
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Other tissues also produce IGF ligands that act in a paracrine or autocrine manner (>>3<<). IGF ligands are bound by insulin-like growth factor binding proteins (IGFBP1-6) (4). While IGFBP binding increases ligand stability, IGFBP binding also decreases ligand bioavailability and competes with ligand-receptor binding.
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IGF ligands are bound by insulin-like growth factor binding proteins (IGFBP1-6) (>>4<<). While IGFBP binding increases ligand stability, IGFBP binding also decreases ligand bioavailability and competes with ligand-receptor binding.
n2:mentions
n3:12067807
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IGF1R has high similarity to the insulin receptor (InsR) (>>5<<, 6). Indeed, although the affinities are much lower, IGF1 can bind and activate the InsR while, in turn, insulin can bind and activate IGF1R (7).
n2:mentions
n3:14501110
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IGF1R has high similarity to the insulin receptor (InsR) (5, >>6<<). Indeed, although the affinities are much lower, IGF1 can bind and activate the InsR while, in turn, insulin can bind and activate IGF1R (7).
n2:mentions
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Indeed, although the affinities are much lower, IGF1 can bind and activate the InsR while, in turn, insulin can bind and activate IGF1R (>>7<<). IGF2 binds both receptors with similar affinities. In addition, a fetal form of InsR that has alternate splicing, termed as insulin receptor isoform A (InsR-A), has a high affinity for IGF2. IGF1R and InsR exist primarily as
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n3:2167752
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However, hybrid IGF1R/InsR receptors, consisting of subunits from both receptors, can form and bind all three ligands (>>8<<–13). Therefore, there is much crosstalk and overlap in receptor signaling downstream of IGFs and insulin.
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Insulin receptor substrates 1 and 2 (IRS1 and IRS2), the main signaling adaptors for both IGF1R and InsR, are recruited to the receptor and act as docking sites (>>14<<). IRS1 and IRS2 link the activated receptors to numerous intracellular adaptor proteins and downstream signaling cascades such as PI3K/AKT and RAS/MAPK/ERK1 (15).
n2:mentions
n3:8384986
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IRS1 and IRS2 link the activated receptors to numerous intracellular adaptor proteins and downstream signaling cascades such as PI3K/AKT and RAS/MAPK/ERK1 (>>15<<).
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The PI3K/AKT and RAS/MAPK pathways both facilitate IGF1R-induced resistance to apoptosis (>>16<<). Additionally, IGF1R interacts with 14.3.3 proteins to induce the mitochondrial translocation of Raf (17). All three of these pathways converge to phosphorylate BAD and block apoptosis. Additionally, IGF1R mediates the cell cycle through
n2:mentions
n3:14726697
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Additionally, IGF1R interacts with 14.3.3 proteins to induce the mitochondrial translocation of Raf (>>17<<). All three of these pathways converge to phosphorylate BAD and block apoptosis. Additionally, IGF1R mediates the cell cycle through MAPK/ERK activation. ERK induces proliferation through phosphorylation of transcription factors such as
n2:mentions
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ERK induces proliferation through phosphorylation of transcription factors such as c-Fos and Ets-like transcription factor 1 (Elk-1) (>>18<<). IGF1R signaling also activates c-Myc, JNK, and c-Jun (19). Cell cycle progression is promoted by IGF1R-mediated increases in ribosome activity (20) and expression of cyclins A, B, and D1 (21, 22). These robust anti-apoptotic properties
n2:mentions
n3:14693367
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IGF1R signaling also activates c-Myc, JNK, and c-Jun (>>19<<). Cell cycle progression is promoted by IGF1R-mediated increases in ribosome activity (20) and expression of cyclins A, B, and D1 (21, 22).
n2:mentions
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Cell cycle progression is promoted by IGF1R-mediated increases in ribosome activity (>>20<<) and expression of cyclins A, B, and D1 (21, 22).
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Cell cycle progression is promoted by IGF1R-mediated increases in ribosome activity (20) and expression of cyclins A, B, and D1 (>>21<<, 22). These robust anti-apoptotic properties of IGF1R and cell cycle regulation both play critical roles in promoting IGF1R-mediated tumorigenesis.
n2:mentions
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Cell cycle progression is promoted by IGF1R-mediated increases in ribosome activity (20) and expression of cyclins A, B, and D1 (21, >>22<<). These robust anti-apoptotic properties of IGF1R and cell cycle regulation both play critical roles in promoting IGF1R-mediated tumorigenesis.
n2:mentions
n3:22239439
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igf1 signaling and mammary gland function
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In the mammary gland, GH stimulates IGF1 production from the stroma (>>23<<), and this is enhanced by estradiol (24, 25).
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n3:2351118
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In the mammary gland, GH stimulates IGF1 production from the stroma (23), and this is enhanced by estradiol (>>24<<, 25). IGF-I acts in a paracrine manner to stimulate terminal end bud (TEB) growth and form the ductal structures that extend through the mammary fat pad. Mammary gland development is decreased in IGF1 (−/−) null females (26).
n2:mentions
n3:7867584
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In the mammary gland, GH stimulates IGF1 production from the stroma (23), and this is enhanced by estradiol (24, >>25<<). IGF-I acts in a paracrine manner to stimulate terminal end bud (TEB) growth and form the ductal structures that extend through the mammary fat pad. Mammary gland development is decreased in IGF1 (−/−) null females (26). Interestingly,
n2:mentions
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Mammary gland development is decreased in IGF1 (−/−) null females (>>26<<). Interestingly, IGF1 produced within the mammary gland is more potent at stimulating mammary growth than circulating IGF1 derived from the liver (27).
n2:mentions
n3:10537134
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Interestingly, IGF1 produced within the mammary gland is more potent at stimulating mammary growth than circulating IGF1 derived from the liver (>>27<<). The IGF1 deficiency in IGF1 (−/−) null mice can be rescued by continuous 5-day injections of the des-IGF1 variant. Longer treatments with IGF1 plus estradiol enhance TEB formation and ductal morphogenesis. Interestingly, treatment with
n2:mentions
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Interestingly, treatment with GH and estradiol does not restore development in IGF1-null mice, indicating the necessity of IGF1 for the full function and stimulation by these hormones (>>26<<).
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Reconstitution assays using IGF1R-deficient embryonic mammary buds demonstrate decreased growth potential and cell proliferation during morphogenesis (>>28<<). The reduction in mammary gland morphogenesis observed upon loss of IGF1/IGF1R signaling is a result of decreased cell cycle progression and increased apoptosis (29–31).
n2:mentions
n3:11606462
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The reduction in mammary gland morphogenesis observed upon loss of IGF1/IGF1R signaling is a result of decreased cell cycle progression and increased apoptosis (>>29<<–31).
n2:mentions
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needs to function in cooperation with growth factors such as epidermal growth factor (EGF) and transforming growth factor beta (TGF-B) as well as the IGF1 receptors and binding proteins for efficient signaling and full mammary function (>>32<<).
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the igf pathway in cancer
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Many different alterations in the IGF system promote tumorigenesis: increased IGF1 and IGF2 expression (>>33<<–36), decreased levels of circulating IGFBPs (which increase ligand bioavailability) (37–39), and changes in receptor expression (40, 41).
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Many different alterations in the IGF system promote tumorigenesis: increased IGF1 and IGF2 expression (33–36), decreased levels of circulating IGFBPs (which increase ligand bioavailability) (>>37<<–39), and changes in receptor expression (40, 41).
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Many different alterations in the IGF system promote tumorigenesis: increased IGF1 and IGF2 expression (33–36), decreased levels of circulating IGFBPs (which increase ligand bioavailability) (37–39), and changes in receptor expression (>>40<<, 41).
n2:mentions
n3:10995803
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different alterations in the IGF system promote tumorigenesis: increased IGF1 and IGF2 expression (33–36), decreased levels of circulating IGFBPs (which increase ligand bioavailability) (37–39), and changes in receptor expression (40, >>41<<).
n2:mentions
n3:21540285
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In breast cancer, 15% of TCGA-documented breast cancers (>>42<<) contain genomic alterations in the IGF pathway. These alterations consist mainly of amplification and are generally rare with only IGF1R and IRS2 showing amplification in >5% of cases.
n2:mentions
n3:23000897
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In particular, germline polymorphisms in IGF1, IGF1R, and IGFBP3 are associated with increased risk of breast (>>43<<–45), prostate (46–48), lung (49), and pancreatic (50) cancers.
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In particular, germline polymorphisms in IGF1, IGF1R, and IGFBP3 are associated with increased risk of breast (43–45), prostate (>>46<<–48), lung (49), and pancreatic (50) cancers.
n2:mentions
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In particular, germline polymorphisms in IGF1, IGF1R, and IGFBP3 are associated with increased risk of breast (43–45), prostate (46–48), lung (>>49<<), and pancreatic (50) cancers.
n2:mentions
n3:16049980
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In particular, germline polymorphisms in IGF1, IGF1R, and IGFBP3 are associated with increased risk of breast (43–45), prostate (46–48), lung (49), and pancreatic (>>50<<) cancers.
n2:mentions
n3:20416304
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For example, tumor tissue microarrays show that 87% of primary breast tumors express IGF1R (>>51<<); however, the active phosphorylated form of IGF1R/InsR, as measured by immunohistochemistry (IHC), is only present in roughly 50% of breast cancers where it correlates with poor survival (52).
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87% of primary breast tumors express IGF1R (51); however, the active phosphorylated form of IGF1R/InsR, as measured by immunohistochemistry (IHC), is only present in roughly 50% of breast cancers where it correlates with poor survival (>>52<<). We examined IGF pathway activity by combining IGF-regulated mRNA levels into an “IGF gene signature.
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” Breast tumors expressing the IGF1 gene signature significantly correlate with numerous poor prognostic factors and expression of this signature is one of the strongest indicators of poor disease outcome (>>53<<).
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igf1r across breast cancer subtypes
n5:contains
_:vb40684636 _:vb40684637 _:vb40684632 _:vb40684633 _:vb40684634 _:vb40684635 _:vb40684628 _:vb40684629 _:vb40684630 _:vb40684631 _:vb40684624 _:vb40684625 _:vb40684626 _:vb40684627 _:vb40684620 _:vb40684621 _:vb40684622 _:vb40684623 _:vb40684616 _:vb40684617 _:vb40684618 _:vb40684619 _:vb40684612 _:vb40684613 _:vb40684614 _:vb40684615 _:vb40684608 _:vb40684609 _:vb40684610 _:vb40684611 _:vb40684572 _:vb40684573 _:vb40684574 _:vb40684575 _:vb40684568 _:vb40684569 _:vb40684570 _:vb40684571 _:vb40684564 _:vb40684565 _:vb40684566 _:vb40684567 _:vb40684560 _:vb40684561 _:vb40684562 _:vb40684563 _:vb40684559 _:vb40684604 _:vb40684605 _:vb40684606 _:vb40684607 _:vb40684600 _:vb40684601 _:vb40684602 _:vb40684603 _:vb40684596 _:vb40684597 _:vb40684598 _:vb40684599 _:vb40684592 _:vb40684593 _:vb40684594 _:vb40684595 _:vb40684588 _:vb40684589 _:vb40684590 _:vb40684591 _:vb40684584 _:vb40684585 _:vb40684586 _:vb40684587 _:vb40684580 _:vb40684581 _:vb40684582 _:vb40684583 _:vb40684576 _:vb40684577 _:vb40684578 _:vb40684579
Subject Item
_:vb40684559
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The current molecular subtypes include luminal A, luminal B, ERBB2-like, triple negative/basal-like, claudin-low, and normal-like (>>54<<, 55). Each subtype can also be further classified into more defined subgroups.
n2:mentions
n3:11553815
Subject Item
_:vb40684560
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n2:Context
rdf:value
The current molecular subtypes include luminal A, luminal B, ERBB2-like, triple negative/basal-like, claudin-low, and normal-like (54, >>55<<). Each subtype can also be further classified into more defined subgroups.
n2:mentions
n3:24250234
Subject Item
_:vb40684561
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For an overview of IGF pathway expression across the breast cancer molecular subtypes, we analyzed TCGA data (>>42<<) (Figure 2).
n2:mentions
n3:23000897
Subject Item
_:vb40684562
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The expressions of the indicated genes from tumors (columns) with calculated PAM50 scores (>>42<<) were extracted, log2 transformed, median centered for each gene (rows), and a heatmap was generated using MeV.
n2:mentions
n3:23000897
Subject Item
_:vb40684563
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Luminal subtypes tend to be hormone receptor positive (ER+, PR+) and comprise ~50% (luminal A) and ~10–20% (luminal B) of all breast cancer cases (>>56<<). Luminal A tumors have the best overall prognosis. Luminal B tumors are similar to luminal A tumors, but are more aggressive (higher grade) and are typically diagnosed at a younger age with higher reoccurrence rates. Hormone therapies (e.
n2:mentions
n3:22178455
Subject Item
_:vb40684564
rdf:type
n2:Context
rdf:value
Estrogen receptor α is a major regulator of IGF signaling, due in part to transcriptional activation of IGF1R and many other IGF signaling components such as IRS1 (>>57<<–59). Consistent with this, the hormonally driven luminal subtypes tend to have higher levels of IGF1R and IRS expression as opposed to tumors that are less hormonally driven (triple negative and ERBB2+) (60, 61).
n2:mentions
n3:10188734 n3:10319328 n3:17170218
Subject Item
_:vb40684565
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Consistent with this, the hormonally driven luminal subtypes tend to have higher levels of IGF1R and IRS expression as opposed to tumors that are less hormonally driven (triple negative and ERBB2+) (>>60<<, 61). IGF1R is expressed in 52 and 84% of Luminal A and 57.5 and 76% of Luminal B tumors, respectively (62, 63). IGF1R expression does not affect breast cancer specific survival in luminal A tumors. Interestingly, luminal B tumors with
n2:mentions
n3:21217522
Subject Item
_:vb40684566
rdf:type
n2:Context
rdf:value
Consistent with this, the hormonally driven luminal subtypes tend to have higher levels of IGF1R and IRS expression as opposed to tumors that are less hormonally driven (triple negative and ERBB2+) (60, >>61<<). IGF1R is expressed in 52 and 84% of Luminal A and 57.5 and 76% of Luminal B tumors, respectively (62, 63). IGF1R expression does not affect breast cancer specific survival in luminal A tumors. Interestingly, luminal B tumors with higher
n2:mentions
n3:22489698
Subject Item
_:vb40684567
rdf:type
n2:Context
rdf:value
IGF1R is expressed in 52 and 84% of Luminal A and 57.5 and 76% of Luminal B tumors, respectively (>>62<<, 63). IGF1R expression does not affect breast cancer specific survival in luminal A tumors. Interestingly, luminal B tumors with higher total IGF1R levels have significantly better prognosis than those with low levels of IGF1R (62). Law
n2:mentions
n3:21574055
Subject Item
_:vb40684568
rdf:type
n2:Context
rdf:value
IGF1R is expressed in 52 and 84% of Luminal A and 57.5 and 76% of Luminal B tumors, respectively (62, >>63<<). IGF1R expression does not affect breast cancer specific survival in luminal A tumors. Interestingly, luminal B tumors with higher total IGF1R levels have significantly better prognosis than those with low levels of IGF1R (62). Law et al.
n2:mentions
n3:25013431
Subject Item
_:vb40684569
rdf:type
n2:Context
rdf:value
Interestingly, luminal B tumors with higher total IGF1R levels have significantly better prognosis than those with low levels of IGF1R (>>62<<). Law et al. demonstrated that roughly 50% of all luminal tumors show phosphorylated, and presumably active, IGF1R (52). As IGF1R is upregulated by ERα, the better prognosis of IGF1R-expressing luminal tumors may be associated with the
n2:mentions
n3:21574055
Subject Item
_:vb40684570
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n2:Context
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Law et al. demonstrated that roughly 50% of all luminal tumors show phosphorylated, and presumably active, IGF1R (>>52<<). As IGF1R is upregulated by ERα, the better prognosis of IGF1R-expressing luminal tumors may be associated with the use of ER-targeted therapies.
n2:mentions
n3:19074892
Subject Item
_:vb40684571
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Estrogen receptor α and the IGF pathway show dynamic and intricate crosstalk, resulting in bidirectional regulation of expression and activity (>>64<<). ERα transcriptionally upregulates IGF1R expression. IGF1R transcriptionally upregulates ERα in an mTOR/S6K1-dependent manner and increases ERα phosphorylation to stimulate transcriptional activity (65, 66).
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n3:24189571
Subject Item
_:vb40684572
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n2:Context
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IGF1R transcriptionally upregulates ERα in an mTOR/S6K1-dependent manner and increases ERα phosphorylation to stimulate transcriptional activity (>>65<<, 66). Importantly, during endocrine resistance, converging growth factor signaling on the PI3K/AKT and MAPK/ERK pathways bypass the need for ERα activity (67–69). Surprisingly, however, use of anti-IGF1R therapy in the setting of
n2:mentions
n3:21292829
Subject Item
_:vb40684573
rdf:type
n2:Context
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IGF1R transcriptionally upregulates ERα in an mTOR/S6K1-dependent manner and increases ERα phosphorylation to stimulate transcriptional activity (65, >>66<<). Importantly, during endocrine resistance, converging growth factor signaling on the PI3K/AKT and MAPK/ERK pathways bypass the need for ERα activity (67–69). Surprisingly, however, use of anti-IGF1R therapy in the setting of endocrine
n2:mentions
n3:25362932
Subject Item
_:vb40684574
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Importantly, during endocrine resistance, converging growth factor signaling on the PI3K/AKT and MAPK/ERK pathways bypass the need for ERα activity (>>67<<–69). Surprisingly, however, use of anti-IGF1R therapy in the setting of endocrine resistance does not improve prognosis (70).
n2:mentions
n3:21595894 n3:23119004
Subject Item
_:vb40684575
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Surprisingly, however, use of anti-IGF1R therapy in the setting of endocrine resistance does not improve prognosis (>>70<<).
n2:mentions
n3:23414585
Subject Item
_:vb40684576
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Consistent with its ERα-dependent regulation, IGF1R levels are reduced in many tamoxifen- and aromatase inhibitor-resistant cell and mouse tumor models (>>71<<–73) as well as patient tumors (74).
n2:mentions
n3:18245484 n3:16037379 n3:14713268
Subject Item
_:vb40684577
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Consistent with its ERα-dependent regulation, IGF1R levels are reduced in many tamoxifen- and aromatase inhibitor-resistant cell and mouse tumor models (71–73) as well as patient tumors (>>74<<). However, the remaining IGF1R is strongly phosphorylated with hyperactive IGF1R/InsR/PI3K/AKT/mTOR signaling beyond pre-resistance levels, suggesting that the cells/tumors acquire resistance through an IGF1R-directed mechanism even in
n2:mentions
n3:24525703
Subject Item
_:vb40684578
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strongly phosphorylated with hyperactive IGF1R/InsR/PI3K/AKT/mTOR signaling beyond pre-resistance levels, suggesting that the cells/tumors acquire resistance through an IGF1R-directed mechanism even in cases of reduced IGF1R levels (69, >>73<<). Furthermore, the Yee lab has shown that while IGF1R is reduced in tamoxifen resistant breast cancer cells, InsR is still expressed and able to signal via insulin to promote growth (75).
n2:mentions
n3:18245484
Subject Item
_:vb40684579
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Furthermore, the Yee lab has shown that while IGF1R is reduced in tamoxifen resistant breast cancer cells, InsR is still expressed and able to signal via insulin to promote growth (>>75<<).
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n3:22573715
Subject Item
_:vb40684580
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Increased GPER expression is associated with increased risk of metastasis and poor survival (>>76<<). Both IGF1 and insulin upregulate GPER expression through the c-Fos/AP1 pathway. IGF1 and insulin transactivate GPER to promote migration and proliferation (77, 78). ERα is required for IGF1-induced transactivation of GPER (77).
n2:mentions
n3:19902352
Subject Item
_:vb40684581
rdf:type
n2:Context
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IGF1 and insulin transactivate GPER to promote migration and proliferation (>>77<<, 78). ERα is required for IGF1-induced transactivation of GPER (77). Interestingly, GPER expression increases in tumors treated with tamoxifen (79) and correlates with a poorer prognosis specifically in tamoxifen treated patients (79–82).
n2:mentions
n3:22430216
Subject Item
_:vb40684582
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n2:Context
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IGF1 and insulin transactivate GPER to promote migration and proliferation (77, >>78<<). ERα is required for IGF1-induced transactivation of GPER (77). Interestingly, GPER expression increases in tumors treated with tamoxifen (79) and correlates with a poorer prognosis specifically in tamoxifen treated patients (79–82).
n2:mentions
n3:25012984
Subject Item
_:vb40684583
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n2:Context
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ERα is required for IGF1-induced transactivation of GPER (>>77<<). Interestingly, GPER expression increases in tumors treated with tamoxifen (79) and correlates with a poorer prognosis specifically in tamoxifen treated patients (79–82).
n2:mentions
n3:22430216
Subject Item
_:vb40684584
rdf:type
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Interestingly, GPER expression increases in tumors treated with tamoxifen (>>79<<) and correlates with a poorer prognosis specifically in tamoxifen treated patients (79–82).
n2:mentions
n3:21607586
Subject Item
_:vb40684585
rdf:type
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Interestingly, GPER expression increases in tumors treated with tamoxifen (79) and correlates with a poorer prognosis specifically in tamoxifen treated patients (>>79<<–82). These results suggest that GPER may be a potential pathway for IGF1- and insulin-induced tamoxifen resistance.
n2:mentions
n3:24715381 n3:21607586 n3:19911269 n3:24289103
Subject Item
_:vb40684586
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Several in vitro studies suggest that biomarker selection is critical for identifying the tumors that will respond to IGF1R inhibitors (>>70<<, 83).
n2:mentions
n3:23414585
Subject Item
_:vb40684587
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Several in vitro studies suggest that biomarker selection is critical for identifying the tumors that will respond to IGF1R inhibitors (70, >>83<<).
n2:mentions
n3:18790743
Subject Item
_:vb40684588
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This was noted in Phase I trials of an mTOR inhibitor and validated in many preclinical studies (>>84<<). For example, inhibition of AKT in long-term estrogen deprived cell lines results in positive feedback that upregulates several upstream growth factor proteins through FoxO and ERα-regulated transcription, including IGF1R and IGF ligands
n2:mentions
n3:16452206
Subject Item
_:vb40684589
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example, inhibition of AKT in long-term estrogen deprived cell lines results in positive feedback that upregulates several upstream growth factor proteins through FoxO and ERα-regulated transcription, including IGF1R and IGF ligands (>>85<<). Combined inhibition of IGF1R/IR along with AKT inhibition and ER deprivation enhances the anti-tumor effect in vivo (85).
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n3:23844554
Subject Item
_:vb40684590
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Combined inhibition of IGF1R/IR along with AKT inhibition and ER deprivation enhances the anti-tumor effect in vivo (>>85<<). The ability of the pathway to autoregulate and compensate for ER downregulation appears to be the cause for endocrine therapeutic resistance. The only way to impede resistance may be through inhibition of the overarching converging
n2:mentions
n3:23844554
Subject Item
_:vb40684591
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ERBB2 (HER2)-like tumors comprise ~15% of breast cancers and are typically hormone receptor negative with a 40% probability of p53 mutation (>>56<<). The ERBB2-like subtype shows poorer prognosis than luminal tumors, with early age of onset, higher tumor grade, and lymph node positivity.
n2:mentions
n3:22178455
Subject Item
_:vb40684592
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About 10–20% of ERBB2+ tumors express IGF1R protein (>>62<<, 63). Active phosphorylated IGF1R/IR is found in 49% (86) and 64% (52) of ERBB2+ tumors.
n2:mentions
n3:21574055
Subject Item
_:vb40684593
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n2:Context
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About 10–20% of ERBB2+ tumors express IGF1R protein (62, >>63<<). Active phosphorylated IGF1R/IR is found in 49% (86) and 64% (52) of ERBB2+ tumors.
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n3:25013431
Subject Item
_:vb40684594
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Active phosphorylated IGF1R/IR is found in 49% (>>86<<) and 64% (52) of ERBB2+ tumors.
n2:mentions
n3:23117852
Subject Item
_:vb40684595
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Active phosphorylated IGF1R/IR is found in 49% (86) and 64% (>>52<<) of ERBB2+ tumors.
n2:mentions
n3:19074892
Subject Item
_:vb40684596
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Brown et al. found phosphorylated IGF1R/IR does not correlate with prognosis in trastuzumab-treated ERBB2+ tumors (>>86<<). However, Yerushalmi et al. observed that ERBB2+ tumors expressing higher total IGF1R protein levels have decreased breast cancer specific survival compared to the lower IGF1R-expressing ERBB2+ counterparts (62). In this study, these
n2:mentions
n3:23117852
Subject Item
_:vb40684597
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However, Yerushalmi et al. observed that ERBB2+ tumors expressing higher total IGF1R protein levels have decreased breast cancer specific survival compared to the lower IGF1R-expressing ERBB2+ counterparts (>>62<<). In this study, these ERBB2-enriched tumors are the only subtype presenting a low patient prognosis in correlation with IGF1R expression (62).
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n3:21574055
Subject Item
_:vb40684598
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In this study, these ERBB2-enriched tumors are the only subtype presenting a low patient prognosis in correlation with IGF1R expression (>>62<<).
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n3:21574055
Subject Item
_:vb40684599
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ERBB2-postive tumors expressing strong IGF1R membrane staining are less likely to respond to trastuzumab and vinorelbine than those with negative or low IGF1R protein expression (>>87<<). Other studies do not indicate a correlation between IGF1R protein expression and trastuzumab response (86, 88, 89) unless IGF1R expression is combined expression of downstream IGF1R signaling effectors, such as PI3K or mTOR (88).
n2:mentions
n3:17317830
Subject Item
_:vb40684600
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Other studies do not indicate a correlation between IGF1R protein expression and trastuzumab response (>>86<<, 88, 89) unless IGF1R expression is combined expression of downstream IGF1R signaling effectors, such as PI3K or mTOR (88).
n2:mentions
n3:23117852
Subject Item
_:vb40684601
rdf:type
n2:Context
rdf:value
Other studies do not indicate a correlation between IGF1R protein expression and trastuzumab response (86, >>88<<, 89) unless IGF1R expression is combined expression of downstream IGF1R signaling effectors, such as PI3K or mTOR (88).
n2:mentions
n3:15305194
Subject Item
_:vb40684602
rdf:type
n2:Context
rdf:value
Other studies do not indicate a correlation between IGF1R protein expression and trastuzumab response (86, 88, >>89<<) unless IGF1R expression is combined expression of downstream IGF1R signaling effectors, such as PI3K or mTOR (88).
n2:mentions
n3:16184380
Subject Item
_:vb40684603
rdf:type
n2:Context
rdf:value
Other studies do not indicate a correlation between IGF1R protein expression and trastuzumab response (86, 88, 89) unless IGF1R expression is combined expression of downstream IGF1R signaling effectors, such as PI3K or mTOR (>>88<<).
n2:mentions
n3:15305194
Subject Item
_:vb40684604
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n2:Context
rdf:value
Unlike clinical data, in vitro breast cancer cell line data suggest a strong correlation between increased IGF1R activity and trastuzumab-resistance (>>90<<–93). Interestingly, miRNAs, which typically inhibit IGF1R, show decreased expression upon trastuzumab-resistance (93, 94) and providing one possible mechanism of IGF1R upregulation.
n2:mentions
n3:16849573 n3:20664936 n3:22830017 n3:24655723
Subject Item
_:vb40684605
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Interestingly, miRNAs, which typically inhibit IGF1R, show decreased expression upon trastuzumab-resistance (>>93<<, 94) and providing one possible mechanism of IGF1R upregulation.
n2:mentions
n3:24655723
Subject Item
_:vb40684606
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Interestingly, miRNAs, which typically inhibit IGF1R, show decreased expression upon trastuzumab-resistance (93, >>94<<) and providing one possible mechanism of IGF1R upregulation.
n2:mentions
n3:24571711
Subject Item
_:vb40684607
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In trastuzumab-resistant cell line models, IGF1R forms a complex with ERBB2, and even a triplex with ERBB3 (>>95<<–97). This heterodimer/trimer promotes crosstalk between the growth receptor pathways. For example, IGF1-induced IGF1R phosphorylation leads to ligand-independent phosphorylation of ERBB2, which circumvents trastuzumab antibody inhibition
n2:mentions
n3:20103628 n3:16322262 n3:21862872
Subject Item
_:vb40684608
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For example, IGF1-induced IGF1R phosphorylation leads to ligand-independent phosphorylation of ERBB2, which circumvents trastuzumab antibody inhibition and leads to an ERBB2-based mechanism of resistance (>>95<<, 98). In trastuzumab-resistant cells, IGF1R-promoted ERBB2 phosphorylation and IGF1R-induced invasion are mediated by Src and FoxM1 (98). Co-targeting ERBB2 and IGF1R reduces Erk/AKT activation, cell proliferation, in vitro invasion, and
n2:mentions
n3:16322262
Subject Item
_:vb40684609
rdf:type
n2:Context
rdf:value
For example, IGF1-induced IGF1R phosphorylation leads to ligand-independent phosphorylation of ERBB2, which circumvents trastuzumab antibody inhibition and leads to an ERBB2-based mechanism of resistance (95, >>98<<). In trastuzumab-resistant cells, IGF1R-promoted ERBB2 phosphorylation and IGF1R-induced invasion are mediated by Src and FoxM1 (98). Co-targeting ERBB2 and IGF1R reduces Erk/AKT activation, cell proliferation, in vitro invasion, and
n2:mentions
n3:25391374
Subject Item
_:vb40684610
rdf:type
n2:Context
rdf:value
In trastuzumab-resistant cells, IGF1R-promoted ERBB2 phosphorylation and IGF1R-induced invasion are mediated by Src and FoxM1 (>>98<<). Co-targeting ERBB2 and IGF1R reduces Erk/AKT activation, cell proliferation, in vitro invasion, and xenograft tumor growth to a greater extent than targeting either receptor individually (98, 99). Interestingly, treating
n2:mentions
n3:25391374
Subject Item
_:vb40684611
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n2:Context
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Co-targeting ERBB2 and IGF1R reduces Erk/AKT activation, cell proliferation, in vitro invasion, and xenograft tumor growth to a greater extent than targeting either receptor individually (>>98<<, 99). Interestingly, treating trastuzumab-resistant cells with metformin re-sensitizes cells by disrupting the ERBB/IGF1R complexes (97), again strongly suggesting that a combined therapy would hold promise for patients with ERBB2+ breast
n2:mentions
n3:25391374
Subject Item
_:vb40684612
rdf:type
n2:Context
rdf:value
Co-targeting ERBB2 and IGF1R reduces Erk/AKT activation, cell proliferation, in vitro invasion, and xenograft tumor growth to a greater extent than targeting either receptor individually (98, >>99<<). Interestingly, treating trastuzumab-resistant cells with metformin re-sensitizes cells by disrupting the ERBB/IGF1R complexes (97), again strongly suggesting that a combined therapy would hold promise for patients with ERBB2+ breast
n2:mentions
n3:24227890
Subject Item
_:vb40684613
rdf:type
n2:Context
rdf:value
Interestingly, treating trastuzumab-resistant cells with metformin re-sensitizes cells by disrupting the ERBB/IGF1R complexes (>>97<<), again strongly suggesting that a combined therapy would hold promise for patients with ERBB2+ breast tumors.
n2:mentions
n3:21862872
Subject Item
_:vb40684614
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Approximately 75% of TNBCs have a basal-like phenotype (>>56<<). Most BRCA-mutant tumors fall into this subtype (100).
n2:mentions
n3:22178455
Subject Item
_:vb40684615
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Most BRCA-mutant tumors fall into this subtype (>>100<<). TNBCs are defined by the absence of ER, PR, and ERBB2.
n2:mentions
n3:17016441
Subject Item
_:vb40684616
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Women of African descent are three times more likely to have TNBC: 30% of breast cancers diagnosed in African-American women are TN as compared to 11–13% of non-African-American women (>>101<<–103). Interestingly, African-American women have higher IGF1R expression in normal breast tissue while Caucasian-Americans have higher levels of IGF2R (104).
n2:mentions
n3:16757721 n3:23012306 n3:19320967
Subject Item
_:vb40684617
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Interestingly, African-American women have higher IGF1R expression in normal breast tissue while Caucasian-Americans have higher levels of IGF2R (>>104<<). This differential IGF1R/IGF2R expression may explain the increased occurrence of the more aggressive TNBC subtype in African-American women. Although IGF1R levels are similar between normal and malignant African-American breast tissues,
n2:mentions
n3:20347606
Subject Item
_:vb40684618
rdf:type
n2:Context
rdf:value
Although IGF1R levels are similar between normal and malignant African-American breast tissues, phosphorylation of IGF1R and its downstream effectors are significantly higher in the malignant samples (>>104<<). Consequently, IGF1 signaling and proliferation (detected by gene expression profiling) are higher in TNBCs from African-American women compared to European-American (51). These studies underscore the significance of IGF1R in TNBC.
n2:mentions
n3:20347606
Subject Item
_:vb40684619
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Consequently, IGF1 signaling and proliferation (detected by gene expression profiling) are higher in TNBCs from African-American women compared to European-American (>>51<<). These studies underscore the significance of IGF1R in TNBC.
n2:mentions
n3:14729636
Subject Item
_:vb40684620
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About 22–46% of TNBCs express IGF1R protein (>>52<<, 62, 63) and this expression correlates with shorter survival (105).
n2:mentions
n3:19074892
Subject Item
_:vb40684621
rdf:type
n2:Context
rdf:value
About 22–46% of TNBCs express IGF1R protein (52, >>62<<, 63) and this expression correlates with shorter survival (105).
n2:mentions
n3:21574055
Subject Item
_:vb40684622
rdf:type
n2:Context
rdf:value
About 22–46% of TNBCs express IGF1R protein (52, 62, >>63<<) and this expression correlates with shorter survival (105).
n2:mentions
n3:25013431
Subject Item
_:vb40684623
rdf:type
n2:Context
rdf:value
About 22–46% of TNBCs express IGF1R protein (52, 62, 63) and this expression correlates with shorter survival (>>105<<). The IGF1 gene signature correlates with expression signatures of TNBC tumors and cell lines (106) where both sample types are responsive to IGF1 signaling, promoting proliferation, and cell survival (107).
n2:mentions
n3:21107683
Subject Item
_:vb40684624
rdf:type
n2:Context
rdf:value
The IGF1 gene signature correlates with expression signatures of TNBC tumors and cell lines (>>106<<) where both sample types are responsive to IGF1 signaling, promoting proliferation, and cell survival (107).
n2:mentions
n3:21177763
Subject Item
_:vb40684625
rdf:type
n2:Context
rdf:value
The IGF1 gene signature correlates with expression signatures of TNBC tumors and cell lines (106) where both sample types are responsive to IGF1 signaling, promoting proliferation, and cell survival (>>107<<).
n2:mentions
n3:21677874
Subject Item
_:vb40684626
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n2:Context
rdf:value
We demonstrated that TNBC cell lines and a primary tumor xenograft are sensitive to the anti-IGF-IR/InsR tyrosine kinase inhibitor BMS-754807 (>>106<<). Surprisingly, expression of a dominant-negative IGF1R during MMTV-Wnt1-mediated tumorigenesis accelerates mammary tumor formation and promotes aggressiveness (108). Interestingly, these tumors possess IGF2 signaling as well as a
n2:mentions
n3:21177763
Subject Item
_:vb40684627
rdf:type
n2:Context
rdf:value
Surprisingly, expression of a dominant-negative IGF1R during MMTV-Wnt1-mediated tumorigenesis accelerates mammary tumor formation and promotes aggressiveness (>>108<<). Interestingly, these tumors possess IGF2 signaling as well as a suggested role for InsR signaling. Additional studies demonstrate that IGF1R inhibition does not abrogate IGF-induced phenotypes in the presence of increased IGF2/IGF2R
n2:mentions
n3:25092896
Subject Item
_:vb40684628
rdf:type
n2:Context
rdf:value
Additional studies demonstrate that IGF1R inhibition does not abrogate IGF-induced phenotypes in the presence of increased IGF2/IGF2R signaling (>>109<<). In TCGA patient data, IGF2R expression is significantly higher in basal-like tumors as compared to luminal tumors (Figure 2) (p value <0.001, t-test). Taken together, these studies suggest that IGF1R inhibition may be beneficial in some
n2:mentions
n3:24853185
Subject Item
_:vb40684629
rdf:type
n2:Context
rdf:value
Recently, the G protein estrogen receptor 1 (GPER/GPR30) has been identified as a potential growth regulator of TNBCs (>>110<<, 111). GPER is believed to mediate rapid estrogen response independently of ER; and thus, can drive estrogen-responsive growth even in ER-negative cells.
n2:mentions
n3:22290080
Subject Item
_:vb40684630
rdf:type
n2:Context
rdf:value
Recently, the G protein estrogen receptor 1 (GPER/GPR30) has been identified as a potential growth regulator of TNBCs (110, >>111<<). GPER is believed to mediate rapid estrogen response independently of ER; and thus, can drive estrogen-responsive growth even in ER-negative cells.
n2:mentions
n3:24011568
Subject Item
_:vb40684631
rdf:type
n2:Context
rdf:value
As mentioned above, IGF1 signaling induces GPER expression and GPER promotes IGF1-induced migration and proliferation (>>77<<, 78). More work need to be completed in this area to determine if GPER could be a potential biomarker for anti-IGF1R-responsive TNBCs.
n2:mentions
n3:22430216
Subject Item
_:vb40684632
rdf:type
n2:Context
rdf:value
As mentioned above, IGF1 signaling induces GPER expression and GPER promotes IGF1-induced migration and proliferation (77, >>78<<). More work need to be completed in this area to determine if GPER could be a potential biomarker for anti-IGF1R-responsive TNBCs.
n2:mentions
n3:25012984
Subject Item
_:vb40684633
rdf:type
n2:Context
rdf:value
Most BRCA1 tumors phenocopy TNBC (>>100<<). In line with BRCA1-mediated repression of the IGF1R promoter (112, 113), BRCA1-mutant tumors show elevated IGFIR and IGF1 levels, leading to reduced apoptosis, and enhanced survival (113–115).
n2:mentions
n3:17016441
Subject Item
_:vb40684634
rdf:type
n2:Context
rdf:value
In line with BRCA1-mediated repression of the IGF1R promoter (>>112<<, 113), BRCA1-mutant tumors show elevated IGFIR and IGF1 levels, leading to reduced apoptosis, and enhanced survival (113–115).
n2:mentions
n3:12706836
Subject Item
_:vb40684635
rdf:type
n2:Context
rdf:value
In line with BRCA1-mediated repression of the IGF1R promoter (112, >>113<<), BRCA1-mutant tumors show elevated IGFIR and IGF1 levels, leading to reduced apoptosis, and enhanced survival (113–115).
n2:mentions
n3:17766039
Subject Item
_:vb40684636
rdf:type
n2:Context
rdf:value
In line with BRCA1-mediated repression of the IGF1R promoter (112, 113), BRCA1-mutant tumors show elevated IGFIR and IGF1 levels, leading to reduced apoptosis, and enhanced survival (>>113<<–115). Importantly, inhibition of the IGF1R/PI3K/AKT pathway decreases proliferation in BRCA1-deficient cells (116). These studies suggest IGF1R signaling significantly contributes to tumor cell proliferation and survival in
n2:mentions
n3:17766039 n3:18045956 n3:14710355
Subject Item
_:vb40684637
rdf:type
n2:Context
rdf:value
Importantly, inhibition of the IGF1R/PI3K/AKT pathway decreases proliferation in BRCA1-deficient cells (>>116<<). These studies suggest IGF1R signaling significantly contributes to tumor cell proliferation and survival in BRCA1-deficient breast cancers.
n2:mentions
n3:22739988
Subject Item
_:vb40684638
rdf:type
n5:Section
dc:title
the influence of igf1r on cell potential and cell fate
n5:contains
_:vb40684672 _:vb40684673 _:vb40684639 _:vb40684668 _:vb40684669 _:vb40684670 _:vb40684671 _:vb40684664 _:vb40684665 _:vb40684666 _:vb40684667 _:vb40684660 _:vb40684661 _:vb40684662 _:vb40684663 _:vb40684656 _:vb40684657 _:vb40684658 _:vb40684659 _:vb40684652 _:vb40684653 _:vb40684654 _:vb40684655 _:vb40684648 _:vb40684649 _:vb40684650 _:vb40684651 _:vb40684644 _:vb40684645 _:vb40684646 _:vb40684647 _:vb40684640 _:vb40684641 _:vb40684642 _:vb40684643
Subject Item
_:vb40684639
rdf:type
n2:Context
rdf:value
In human embryonic stem cells, the stem cell niche produces IGF2, which is required for survival and expansion (>>117<<). In neural stem cells, IGF2 is believed to bind and act through the InsR-A rather than IGF1R (118). Conversely, the human embryonic niche relies on the IGF2/IGF1R axis for self renewal and stem cell expansion (117), suggesting the
n2:mentions
n3:17625568
Subject Item
_:vb40684640
rdf:type
n2:Context
rdf:value
In neural stem cells, IGF2 is believed to bind and act through the InsR-A rather than IGF1R (>>118<<). Conversely, the human embryonic niche relies on the IGF2/IGF1R axis for self renewal and stem cell expansion (117), suggesting the necessity of IGF1R-promoted signaling in maintaining the stem cell population. In the hematopoietic and
n2:mentions
n3:24398690
Subject Item
_:vb40684641
rdf:type
n2:Context
rdf:value
Conversely, the human embryonic niche relies on the IGF2/IGF1R axis for self renewal and stem cell expansion (>>117<<), suggesting the necessity of IGF1R-promoted signaling in maintaining the stem cell population.
n2:mentions
n3:17625568
Subject Item
_:vb40684642
rdf:type
n2:Context
rdf:value
muscle-localized IGF1 transgene enhances skeletal muscle regeneration in irradiated mice in part by recruiting proliferating bone marrow-derived cells, increasing stem cell marker populations, and accelerating myogenic differentiation (>>119<<, 120). Additionally in the hematopoietic system, IGF1R levels in newborn umbilical cord blood correlates positively to the total number of hematopoietic stem and progenitor cells (121).
n2:mentions
n3:14745025
Subject Item
_:vb40684643
rdf:type
n2:Context
rdf:value
IGF1 transgene enhances skeletal muscle regeneration in irradiated mice in part by recruiting proliferating bone marrow-derived cells, increasing stem cell marker populations, and accelerating myogenic differentiation (119, >>120<<). Additionally in the hematopoietic system, IGF1R levels in newborn umbilical cord blood correlates positively to the total number of hematopoietic stem and progenitor cells (121).
n2:mentions
n3:16109502
Subject Item
_:vb40684644
rdf:type
n2:Context
rdf:value
Additionally in the hematopoietic system, IGF1R levels in newborn umbilical cord blood correlates positively to the total number of hematopoietic stem and progenitor cells (>>121<<). These studies demonstrate a role for IGF1R in regulation of stem and progenitor cell populations.
n2:mentions
n3:17501995
Subject Item
_:vb40684645
rdf:type
n2:Context
rdf:value
Belfiore summarized in great detail the known pathways and links between the IGF1R pathway and the epithelial-to-mesenchymal transition (EMT) and stem cell-related processes across several tissue types, both normal and cancerous (>>122<<). EMT is a naturally occurring process for remodeling of tissues and wound healing where polarized epithelial cells lose adherence and gain mesenchymal characteristics, including enhanced mobility and matrix invasion.
n2:mentions
n3:24550888
Subject Item
_:vb40684646
rdf:type
n2:Context
rdf:value
Interestingly, cells undergoing EMT also acquire stem cell-associated characteristics such as the capacity for self-renewal, gain of specific gene expression changes and cell surface markers, and ability to initiate tumorigenesis (>>123<<). The gain of these stem cell-associated properties suggests an overlap between EMT and stem cell mechanisms.
n2:mentions
n3:18485877
Subject Item
_:vb40684647
rdf:type
n2:Context
rdf:value
Numerous in vitro studies demonstrate IGF1R as a driver of self renewal, stem cell surface markers, migration, and invasion in both normal and cancerous tissues and tumor initiation in hepatic, lung, prostate, and breast cancers (>>122<<). Each of these studies has begun to reveal the mechanisms of IGF1R-regulated EMT and stem phenotypes.
n2:mentions
n3:24550888
Subject Item
_:vb40684648
rdf:type
n2:Context
rdf:value
Stem-promoting signaling pathways such as Wnt/B-catenin (>>124<<–127), Notch (128–130), and Shh (131, 132) act upstream to increase IGF1R expression with cross talk and regulation at the IGF1R promoter level by Sp1 and HMGA1 (133–136).
n2:mentions
n3:11313952 n3:11035789 n3:20235220 n3:20504360
Subject Item
_:vb40684649
rdf:type
n2:Context
rdf:value
Stem-promoting signaling pathways such as Wnt/B-catenin (124–127), Notch (>>128<<–130), and Shh (131, 132) act upstream to increase IGF1R expression with cross talk and regulation at the IGF1R promoter level by Sp1 and HMGA1 (133–136).
n2:mentions
n3:20154720 n3:21807868 n3:21145317
Subject Item
_:vb40684650
rdf:type
n2:Context
rdf:value
Stem-promoting signaling pathways such as Wnt/B-catenin (124–127), Notch (128–130), and Shh (>>131<<, 132) act upstream to increase IGF1R expression with cross talk and regulation at the IGF1R promoter level by Sp1 and HMGA1 (133–136).
n2:mentions
n3:15195141
Subject Item
_:vb40684651
rdf:type
n2:Context
rdf:value
Stem-promoting signaling pathways such as Wnt/B-catenin (124–127), Notch (128–130), and Shh (131, >>132<<) act upstream to increase IGF1R expression with cross talk and regulation at the IGF1R promoter level by Sp1 and HMGA1 (133–136).
n2:mentions
n3:20389077
Subject Item
_:vb40684652
rdf:type
n2:Context
rdf:value
Stem-promoting signaling pathways such as Wnt/B-catenin (124–127), Notch (128–130), and Shh (131, 132) act upstream to increase IGF1R expression with cross talk and regulation at the IGF1R promoter level by Sp1 and HMGA1 (>>133<<–136). In addition to upstream regulation by these master stem cell master controllers, IGF1R promotes positive downstream feedback through regulation and interaction with the well known EMT and stemness-linked transcription factors Zeb1
n2:mentions
n3:16815029 n3:20335021 n3:12665574 n3:24281069
Subject Item
_:vb40684653
rdf:type
n2:Context
rdf:value
In addition to upstream regulation by these master stem cell master controllers, IGF1R promotes positive downstream feedback through regulation and interaction with the well known EMT and stemness-linked transcription factors Zeb1 (>>137<<), NFκB (138), Snail (138), Twist (139), and p53, Sox2, Oct4, Nanog (140–142). Additionally, the tumor suppressor p53, known for inhibition of many stem cell regulators, inhibits IGF1R (143), which in turn act to downregulate p53.
n2:mentions
n3:18381457
Subject Item
_:vb40684654
rdf:type
n2:Context
rdf:value
to upstream regulation by these master stem cell master controllers, IGF1R promotes positive downstream feedback through regulation and interaction with the well known EMT and stemness-linked transcription factors Zeb1 (137), NFκB (>>138<<), Snail (138), Twist (139), and p53, Sox2, Oct4, Nanog (140–142). Additionally, the tumor suppressor p53, known for inhibition of many stem cell regulators, inhibits IGF1R (143), which in turn act to downregulate p53.
n2:mentions
n3:17296734
Subject Item
_:vb40684655
rdf:type
n2:Context
rdf:value
regulation by these master stem cell master controllers, IGF1R promotes positive downstream feedback through regulation and interaction with the well known EMT and stemness-linked transcription factors Zeb1 (137), NFκB (138), Snail (>>138<<), Twist (139), and p53, Sox2, Oct4, Nanog (140–142). Additionally, the tumor suppressor p53, known for inhibition of many stem cell regulators, inhibits IGF1R (143), which in turn act to downregulate p53.
n2:mentions
n3:17296734
Subject Item
_:vb40684656
rdf:type
n2:Context
rdf:value
by these master stem cell master controllers, IGF1R promotes positive downstream feedback through regulation and interaction with the well known EMT and stemness-linked transcription factors Zeb1 (137), NFκB (138), Snail (138), Twist (>>139<<), and p53, Sox2, Oct4, Nanog (140–142). Additionally, the tumor suppressor p53, known for inhibition of many stem cell regulators, inhibits IGF1R (143), which in turn act to downregulate p53.
n2:mentions
n3:11323435
Subject Item
_:vb40684657
rdf:type
n2:Context
rdf:value
controllers, IGF1R promotes positive downstream feedback through regulation and interaction with the well known EMT and stemness-linked transcription factors Zeb1 (137), NFκB (138), Snail (138), Twist (139), and p53, Sox2, Oct4, Nanog (>>140<<–142). Additionally, the tumor suppressor p53, known for inhibition of many stem cell regulators, inhibits IGF1R (143), which in turn act to downregulate p53.
n2:mentions
n3:23539445 n3:8375929 n3:22473773
Subject Item
_:vb40684658
rdf:type
n2:Context
rdf:value
Additionally, the tumor suppressor p53, known for inhibition of many stem cell regulators, inhibits IGF1R (>>143<<), which in turn act to downregulate p53.
n2:mentions
n3:12821780
Subject Item
_:vb40684659
rdf:type
n2:Context
rdf:value
In human primary breast cancer xenografts, total and phosphorylated IGF1R expression is significantly higher in the CD44+CD24− sorted breast cancer stem cell population compared to the non-CD44+CD24− population (>>144<<). IGF1R expression and upregulated AKT activity are required for maintenance of this population. IGF1R inhibition reduces the aldehyde dehydrogenase+ stem-like population and suppresses mammosphere-forming capacity. Notably, silencing of
n2:mentions
n3:23663564
Subject Item
_:vb40684660
rdf:type
n2:Context
rdf:value
for maintenance of this population. IGF1R inhibition reduces the aldehyde dehydrogenase+ stem-like population and suppresses mammosphere-forming capacity. Notably, silencing of IGF1R reduces tumor initiating ability of the xenografts. (>>144<<). Together this data demonstrate an active role for IGF1R in driving mammary stem-like phenotypes in vitro and in vivo.
n2:mentions
n3:23663564
Subject Item
_:vb40684661
rdf:type
n2:Context
rdf:value
In thyroid tissues, cell lineage differentiation is associated with IGF pathway activation (>>145<<). A similar trend is observed in neural cells. The lineage restricted neural progenitors primarily express IGF1R while the neural stems cells appear to rely more heavily on IGF2 and IR-A signaling (118). These studies suggest that IGF1R
n2:mentions
n3:21123448
Subject Item
_:vb40684662
rdf:type
n2:Context
rdf:value
The lineage restricted neural progenitors primarily express IGF1R while the neural stems cells appear to rely more heavily on IGF2 and IR-A signaling (>>118<<). These studies suggest that IGF1R may be responsible for promoting cell fate, or at the very least, be restricted to maintaining differentiated cells of a specific lineage.
n2:mentions
n3:24398690
Subject Item
_:vb40684663
rdf:type
n2:Context
rdf:value
TEB formation and ductal outgrowth are grossly impaired in IGF1−/− mice (>>26<<), signifying that IGF1 signaling is significant for development and/or maintenance of the mammary stem cell niche.
n2:mentions
n3:10537134
Subject Item
_:vb40684664
rdf:type
n2:Context
rdf:value
While IGF1R-null mice die postnatally before mammary gland development, mammary gland transplantation of embryonic IGF1R-null mammary buds shows reduced ductal growth similar to IGF1-null mice (>>28<<). The IGF pathway is also important in pregnancy and lactation where luminal differentiation is vital. During early pregnancy, alveolar differentiation is reduced in heterozygous IGF1 mice (146). This same lack of alveolar budding and
n2:mentions
n3:11606462
Subject Item
_:vb40684665
rdf:type
n2:Context
rdf:value
During early pregnancy, alveolar differentiation is reduced in heterozygous IGF1 mice (>>146<<). This same lack of alveolar budding and decreased alveolar density is observed in transgenic mice containing a pregnancy-induced kinase-dead IGF1R (147). Thus, the IGF pathway seems to have a role not only in mammary gland stem cell
n2:mentions
n3:16901968
Subject Item
_:vb40684666
rdf:type
n2:Context
rdf:value
This same lack of alveolar budding and decreased alveolar density is observed in transgenic mice containing a pregnancy-induced kinase-dead IGF1R (>>147<<). Thus, the IGF pathway seems to have a role not only in mammary gland stem cell maintenance but also in lineage specification throughout the many stages of mammary gland development.
n2:mentions
n3:21628386
Subject Item
_:vb40684667
rdf:type
n2:Context
rdf:value
In breast cancer, IGF1R expression correlates most strongly with luminal breast cancers (>>60<<, 61). This expression may be a result of ER-driven growth through IGF1R rather than a causative link between IGF1R and the luminal lineage; nevertheless, the presence of IGF1R may still affect cell signaling and perhaps cell lineage. In
n2:mentions
n3:21217522
Subject Item
_:vb40684668
rdf:type
n2:Context
rdf:value
In breast cancer, IGF1R expression correlates most strongly with luminal breast cancers (60, >>61<<). This expression may be a result of ER-driven growth through IGF1R rather than a causative link between IGF1R and the luminal lineage; nevertheless, the presence of IGF1R may still affect cell signaling and perhaps cell lineage. In
n2:mentions
n3:22489698
Subject Item
_:vb40684669
rdf:type
n2:Context
rdf:value
In addition to luminal tumors, IGF1R actively promotes tumor growth and survival in p53 and BRCA1-mutant tumors, which usually emulate the basal-like subtype (>>113<<–115). Although basal-like breast cancers are defined by basal and myoepithelial marker expression (148), they present with a luminal progenitor gene signature (148–152). In support of this luminal link, recent studies suggest
n2:mentions
n3:17766039 n3:18045956 n3:14710355
Subject Item
_:vb40684670
rdf:type
n2:Context
rdf:value
Although basal-like breast cancers are defined by basal and myoepithelial marker expression (>>148<<), they present with a luminal progenitor gene signature (148–152).
n2:mentions
n3:18316557
Subject Item
_:vb40684671
rdf:type
n2:Context
rdf:value
Although basal-like breast cancers are defined by basal and myoepithelial marker expression (148), they present with a luminal progenitor gene signature (>>148<<–152). In support of this luminal link, recent studies suggest BRCA1-associated basal-like tumors derive from a luminal progenitor cell of origin rather than a basally positioned cell (150, 153). Elevated IGF1R expression and signaling in
n2:mentions
n3:18316557 n3:20813035 n3:21047916 n3:18039137 n3:19648928
Subject Item
_:vb40684672
rdf:type
n2:Context
rdf:value
In support of this luminal link, recent studies suggest BRCA1-associated basal-like tumors derive from a luminal progenitor cell of origin rather than a basally positioned cell (>>150<<, 153). Elevated IGF1R expression and signaling in these basal-like tumors appear to have active roles in tumor promotion. Thus, as IGF1R is associated with cell lineage fate, IGF1R signaling may be influencing the gain and loss of lineage
n2:mentions
n3:19648928
Subject Item
_:vb40684673
rdf:type
n2:Context
rdf:value
In support of this luminal link, recent studies suggest BRCA1-associated basal-like tumors derive from a luminal progenitor cell of origin rather than a basally positioned cell (150, >>153<<). Elevated IGF1R expression and signaling in these basal-like tumors appear to have active roles in tumor promotion. Thus, as IGF1R is associated with cell lineage fate, IGF1R signaling may be influencing the gain and loss of lineage
n2:mentions
n3:20804975
Subject Item
_:vb40684674
rdf:type
n5:Section
dc:title
therapeutic targeting of igf1r as an anti-cancer therapy
n5:contains
_:vb40684680 _:vb40684681 _:vb40684676 _:vb40684677 _:vb40684678 _:vb40684679 _:vb40684675
Subject Item
_:vb40684675
rdf:type
n2:Context
rdf:value
In a Phase I trial of the monoclonal antibody, AMG 479, a patient with chemo-refractory Ewing sarcoma had complete remission (>>154<<). In a Phase II trial, 14% of 125 patients with recurrent or refractory sarcoma responded to the monoclonal IGF1R antibody, R1507 (155, 156). In both of these trials, therapy was well tolerated. In contrast, two large NSCLC Phase III
n2:mentions
n3:19786654
Subject Item
_:vb40684676
rdf:type
n2:Context
rdf:value
In a Phase II trial, 14% of 125 patients with recurrent or refractory sarcoma responded to the monoclonal IGF1R antibody, R1507 (>>155<<, 156). In both of these trials, therapy was well tolerated. In contrast, two large NSCLC Phase III trials of figitumumab in combination with either carboplatin and paclitaxel or Tarceva, respectively, were terminated due to lack of
n2:mentions
n3:22025149
Subject Item
_:vb40684677
rdf:type
n2:Context
rdf:value
In a Phase II trial, 14% of 125 patients with recurrent or refractory sarcoma responded to the monoclonal IGF1R antibody, R1507 (155, >>156<<). In both of these trials, therapy was well tolerated. In contrast, two large NSCLC Phase III trials of figitumumab in combination with either carboplatin and paclitaxel or Tarceva, respectively, were terminated due to lack of response
n2:mentions
n3:24797726
Subject Item
_:vb40684678
rdf:type
n2:Context
rdf:value
In contrast, two large NSCLC Phase III trials of figitumumab in combination with either carboplatin and paclitaxel or Tarceva, respectively, were terminated due to lack of response and severe toxicities (>>157<<, 158).
n2:mentions
n3:23054135
Subject Item
_:vb40684679
rdf:type
n2:Context
rdf:value
In contrast, two large NSCLC Phase III trials of figitumumab in combination with either carboplatin and paclitaxel or Tarceva, respectively, were terminated due to lack of response and severe toxicities (157, >>158<<).
n2:mentions
n3:24888810
Subject Item
_:vb40684680
rdf:type
n2:Context
rdf:value
The failure may be a consequence of trial design and not the efficacy of the IGF1R inhibitors themselves (>>159<<). In the Phase III trials, patients were not screened for IGF1R expression, limiting the percent of patients that even had a chance to respond to the therapy. Additionally, monoclonal antibody inhibition is specific to IGF1R and does not
n2:mentions
n3:21717908
Subject Item
_:vb40684681
rdf:type
n2:Context
rdf:value
InsR signaling increases upon IGF1R inhibition, suggesting pathway compensation (>>160<<–163). As touched on throughout the above review, there is also substantial crosstalk between many of the growth factor signaling pathways, including IGFR, EGFR, ErbB2, and ERα. A combinatory therapy approach may be needed for efficient
n2:mentions
n3:20457905 n3:20924128 n3:20610571 n3:17210722
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8
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