A Kinome-Wide Screen Identifies the Insulin/IGF-I Receptor Pathway as a Mechanism of Escape from Hormone Dependence in Breast Cancer

Fox, Emily M.; Miller, Todd W.; Balko, Justin M.; Kuba, María G.; Sánchez, Violeta; Smith, Randall A.; Liu, Shuying; González-Angulo, Ana M.; Mills, Gordon B.; Ye, Fei; Shyr, Yu; Manning, H. Charles; Buck, Elizabeth; Arteaga, Carlos L.

doi:10.1158/0008-5472.can-11-1295

Cited by 146 publications

(115 citation statements)

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“…IGF, insulin-like growth factor; c/c, case-control study; ELISA, enzyme-linked immunosorbent assay; BMI, body mass index; HRT, hormone replacement therapy; OCont, oral contraceptive; IRMA, immunoradiometric assay; NR, not reported. study (20) reported that exogenous hormone use may affect the peptide levels in the IGF signaling pathway, which induced the decrease of circulating IGF-1 concentration.…”

Section: Discussionmentioning

confidence: 99%

Association of circulating insulin-like growth factor 1 and insulin-like growth factor binding protein 3 with the risk of ovarian cancer: A systematic review and meta-analysis

Wang

Bian

Peng

et al. 2015

Molecular and Clinical Oncology

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Abstract. Insulin-like growth factor 1 (IGF-1) and its main binding protein (IGFBP-3) in blood have been associated with the risk of several types of cancer. However, epidemiological studies have inconsistent results regarding the association of circulating IGF-1/IGFBP-3 levels with ovarian cancer risk. A systematic review of the prospective studies was conducted using meta-analysis to evaluate the existing evidence. Pubmed and Embase databases were searched to identify the relevant studies published before May 1, 2014. Four highly qualified studies with a total of 627 cases and 1,358 controls were finally included in the meta-analysis. Random effects meta-analysis was conducted by combining study-specific odds ratios (ORs) of ovarian cancer for the highest verses lowest exposure levels. A dose-response association was further assessed by relating the log of ORs for different exposure levels. As a result, the pooled ORs for the highest verses lowest categories of IGF-1/IGFBP-3 were 0.85 [95% confidence interval (CI), 0.51-1.40]/0.78 (95% CI, 0.43-1.40). In the subgroup analyses, the pooled ORs of IGF-1/IGFBP-3 were 1.89 (95% CI, 0.64-5.59)/1.08 (95% CI, 0.50-2.32) for the subgroup with cases diagnosed at <55 years, and 0.74 (95% CI, 0.50-1.08)/0.98 (95% CI, 0.73-1.33) for the subgroup with cases diagnosed at ≥55 years. No linear association between circulating IGF-1/IGFBP-3 levels and ovarian cancer risk was identified. As no significant association of IGF-1/IGFBP-3 with ovarian cancer risk was identified in the present meta-analysis of existing studies, more studies with greater quality are required in the future.

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Section: Discussionmentioning

confidence: 99%

Association of circulating insulin-like growth factor 1 and insulin-like growth factor binding protein 3 with the risk of ovarian cancer: A systematic review and meta-analysis

Wang

Bian

Peng

et al. 2015

Molecular and Clinical Oncology

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“…18,19 S6K1 is also one of the kinases required for hormoneindependent breast cancer cell proliferation. 48 In addition, mTORC1 serves as an important signaling node for several growth factor signaling pathways that are implicated in endocrine resistance, such as MAPK and PI3K. Thus, mTORC1 hyperactivation by converging stimuli would be targeted by the addition of mTOR inhibitors to endocrine therapy.…”

Section: S6k1 In Er-positivementioning

confidence: 99%

“…P-S6K1 and P-S6 positively correlated with high proliferative index in letrozole-treated patients, indicative of endocrine resistance and poor patient outcome. 48 Since a significant number of patients carry S6K1 amplification and exhibit S6K1 overexpression or overexpression, S6K1 could be utilized as a prognostic marker. Detection of S6K1 expression in breast cancer could be an effective way to target and treat patients most likely to respond to the combination of mTORC1 and endocrine inhibitors.…”

Section: S6k1 In Er-positivementioning

confidence: 99%

“…61 Inhibition of the estrogenic activation of S6K1 may also be the target of action of letrozole, which has been shown to reduce phosphorylation of S6K1 and its targets, p-mTOR Ser2448 and p-S6. 48,73,79 Therefore, maintaining high co-overexpression of both S6K1 and ERα may provide a selective advantage for breast cancer cells and contribute to disregulated proliferation of cells during the progression to carcinogenesis and breast cancer. Finally, S6K1 was revealed as a significant hit in a genome-wide screen for kinases important for growth of MCF7/LTED cells (ER-positive cells selected after long-term estrogen deprivation.…”

Section: Grant Supportmentioning

confidence: 99%

“…Finally, S6K1 was revealed as a significant hit in a genome-wide screen for kinases important for growth of MCF7/LTED cells (ER-positive cells selected after long-term estrogen deprivation. 48 …”

Section: Grant Supportmentioning

confidence: 99%

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The role of S6K1 in ER-positive breast cancer

Holz

2012

Cell Cycle

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T he 40S ribosomal S6 kinase 1 (S6K1) is a conserved serine/threonine protein kinase that belongs to the AGC family of protein kinases, which also includes Akt and many others. S6K1 is the principal kinase effector downstream of the mammalian target of rapamycin complex 1 (mTORC1). S6K1 is sensitive to a wide range of signaling inputs, including growth factors, amino acids, energy levels and hypoxia. S6K1 relays these signals to regulate a growing list of substrates and interacting proteins in control of oncogenic processes, such as cell growth and proliferation, cell survival and apoptosis and cell migration and invasion. Several lines of evidence suggest an important role for S6K1 in estrogen receptor (ER)-positive breast cancer. S6K1 directly phosphorylates and activates ERα. Furthermore, S6K1 expression is estrogenically regulated. Therefore, hyperactivation of mTORC1/ S6K1 signaling may be closely related to ER-positive status in breast cancer and may be utilized as a marker for prognosis and a therapeutic target. IntroductionThe mTORC1 signaling pathway. Since its cloning and biochemical purification almost 20 y ago, mTOR, a conserved protein kinase, emerged as a central node in the plexus coordinating cellular growth and proliferation in response to numerous extracellular cues, including nutrient availability and growth stimuli. In eukaryotic cells, mTOR exists in two complexes. mTORC1 and mTORC2 consist of distinct sets of proteins and perform non-redundant functions. 1 a naturally derived inhibitor of mTORC1 and an inhibitor of cell proliferation, as manifested by its potent immunosuppressive properties and activity against solid tumors. 2 Growth factor signaling to mTORC1 is primarily mediated by the phosphatidylinositol-3 kinase (PI3K) pathway and inactivation of the tuberous sclerosis complex protein TSC2 (tuberin). As illustrated in Figure 1, in response to extracellular activating stimuli, PI3K mediates cell membrane recruitment and activation of the serine/threonine protein kinases phosphatidylinositol-dependent kinase-1 (PDK1) and Akt. 3,4 The lipid phosphatase PTEN opposes the action of PI3K. TSC2 functions as a heterodimer with TSC1 (hamartin) to negatively regulate mTORC1 signaling by acting as a GTPase-activating protein (GAP) for the small GTPase Rheb. 5 Rheb directly binds to mTORC1 and regulates its activity in a GTP-dependent manner. 6 Thus, TSC2 inhibits Rheb-dependent activation of mTORC1. Phosphorylation and inactivation of TSC2 has first been shown to occur via PI3K/Akt. 7 Subsequently, several groups have shown that the Ras/ERK pathway also converges on the TSC1/2 complex. Ras-activated ERK1/2 directly phosphorylates TSC2 at sites different than Akt, resulting in TSC2 inactivation. 8 The downstream effector of ERK, RSK, also phosphorylates TSC2 at a unique site, thus inactivating it. 9 Therefore, TSC2 serves as a convergence point for multiple signaling inputs to mTORC1.Activation of S6K1. S6K1 is one of the best-characterized downstream targets of mTORC1, and rapamycin treatment re...

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Inhibitors of STAT3, β‐catenin, and IGF‐1R sensitize mouse PIK3CA‐mutant breast cancer to PI3K inhibitors

et al. 2017

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Although mutations in the phosphoinositide 3‐kinase catalytic subunit (PIK3CA) are common in breast cancer, PI3K inhibitors alone have shown modest efficacy. We sought to identify additional pathways altered in PIK3CA‐mutant tumors that might be targeted in combination with PI3K inhibitors. We generated two transgenic mouse models expressing the human PIK3CA‐H1047R‐ and the ‐E545K hotspot‐mutant genes in the mammary gland and evaluated their effects on development and tumor formation. Molecular analysis identified pathways altered in these mutant tumors, which were also targeted in multiple cell lines derived from the PIK3CA tumors. Finally, public databases were analyzed to determine whether novel pathways identified in the mouse tumors were altered in human tumors harboring mutant PIK3CA. Mutant mice showed increased branching and delayed involution of the mammary gland compared to parental FVB/N mice. Mammary tumors arose in 30% of the MMTV‐PIK3CA‐H1047R and in 13% of ‐E545K mice. Compared to MMTV‐Her‐2 transgenic mouse mammary tumors, H1047R tumors showed increased upregulation of Wnt/β‐catenin/Axin2, hepatocyte growth factor (Hgf)/Stat3, insulin‐like growth factor 2 (Igf‐2), and Igf‐1R pathways. Inhibitors of STAT3, β‐catenin, and IGF‐1R sensitized H1047R‐derived mouse tumor cells and PIK3CA‐H1047R overexpressing human HS578T breast cancer cells to the cytotoxic effects of PI3K inhibitors. Analysis of The Cancer Genome Atlas database showed that, unlike primary PIK3CA‐wild‐type and HER‐2+ breast carcinomas, PIK3CA‐mutant tumors display increased expression of AXIN2, HGF, STAT3, IGF‐1, and IGF‐2 mRNA and activation of AKT, IGF1‐MTOR, and WNT canonical signaling pathways. Drugs targeting additional pathways that are altered in PIK3CA‐mutant tumors may improve treatment regimens using PI3K inhibitors alone.

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A Kinome-Wide Screen Identifies the Insulin/IGF-I Receptor Pathway as a Mechanism of Escape from Hormone Dependence in Breast Cancer

Cited by 146 publications

References 46 publications

Association of circulating insulin-like growth factor 1 and insulin-like growth factor binding protein 3 with the risk of ovarian cancer: A systematic review and meta-analysis

Association of circulating insulin-like growth factor 1 and insulin-like growth factor binding protein 3 with the risk of ovarian cancer: A systematic review and meta-analysis

The role of S6K1 in ER-positive breast cancer

Inhibitors of STAT3, β‐catenin, and IGF‐1R sensitize mouse PIK3CA‐mutant breast cancer to PI3K inhibitors

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