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Review
. 2015;20(5-6):373-90.
doi: 10.1615/CritRevOncog.v20.i5-6.100.

Estrogen Receptor-β and the Insulin-Like Growth Factor Axis as Potential Therapeutic Targets for Triple-Negative Breast Cancer

Nalo Hamilton  1 , Diana Marquez-Garban  2 , Vei H Mah  3 , Yahya Elshimali  4 , David Elashoff  5 , Edward B Garon  6 , Jaydutt Vadgama  7 , Richard Pietras  2
Affiliations
Review

Estrogen Receptor-β and the Insulin-Like Growth Factor Axis as Potential Therapeutic Targets for Triple-Negative Breast Cancer

Nalo Hamilton et al. Crit Rev Oncog. 2015.

Abstract

Triple-negative breast cancers (TNBCs) lack estrogen receptor-α (ERα), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) amplification and account for almost half of all breast cancer deaths. This breast cancer subtype largely affects women who are premenopausal, African-American, or have BRCA1/2 mutations. Women with TNBC are plagued with higher rates of distant metastasis that significantly diminish their overall survival and quality of life. Due to their poor response to chemotherapy, patients with TNBC would significantly benefit from development of new targeted therapeutics. Research suggests that the insulin-like growth factor (IGF) family and estrogen receptor beta-1 (ERβ1), due to their roles in metabolism and cellular regulation, might be attractive targets to pursue for TNBC management. Here, we review the current state of the science addressing the roles of ERβ1 and the IGF family in TNBC. Further, the potential benefit of metformin treatment in patients with TNBC as well as areas of therapeutic potential in the IGF-ERβ1 pathway are highlighted.

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Figures

FIG. 1
FIG. 1
ERβ1 expression in archival TNBC specimens detected by immunohistochemisry using anti-ERβ1 antibody (PPG5/10, AbDSerotec). A representative example of ERβ1 immunostaining is shown using tumor and neighboring, nonmalignant tissue from the same patient. (a) Nuclear and cytoplasmic staining are shown on a representative specimen of TNBC at low magnification. (b) The same specimen from the previous panel shows nuclear and cytoplasmic staining at higher magnification as indicated by arrows. (c) Expression of nuclear ERβ1 is also present in neighboring normal tissue of the same patient tumor tissue displayed in panels (a) and (b). (d) A different TNBC tumor specimen that does not express ERβ1 is shown for comparison. Antibody binding was detected by using diaminobenzidine (DAKO). Sections were counterstained with Harris hematoxylin. (Reprinted with permission from the Hindawi Publishing Corporation, Copyright 2015).
FIG. 2
FIG. 2
Tumor expression of ERβ1 associates with reduced overall survival (OS) in TNBC specimens from the clinic. TNBCs from three African-American and 11 Caucasian women were scored for nuclear (using IHC with validated antibody anti-ERβ1 antibody PPG5/10 (AbDSerotec). Allred scores >2 are denoted as positive. In this group of patients with advanced TNBC, overall survival (OS) was significantly worse for TNBC patients with high nuclear ERβ1 (positive) as compared to those with low (negative) ERβ1 (p < 0.001). We note that TNBCs from all three African-American women were high ERβ1-positive. (Reprinted with permission from the Hindawi Publishing Corporation, Copyright 2015).
FIG. 3
FIG. 3
Interactions of IGF and ERβ signaling pathways in malignancy. TNBC proliferation is regulated closely by a complex network of growth factor signaling pathways. It is well known that obesity and diabetes can increase insulin and insulin-like growth factor signaling, which in turn may stimulate specific receptors to drive the activation of downstream signaling pathways in TNBC. IGF-1 and IGF-2 bind receptors activating PI3K and Akt signaling and downstream mTOR activation that promotes protein synthesis, cell proliferation, and inhibition of apoptosis. In addition, EGFR is frequently overexpressed in TNBC and is stimulated by binding with epidermal growth factor (EGF). Cross-communication of EGFR signaling with ERβ may induce downstream signaling that contributes to tumor cell survival. ERβ is activated by estrogen (E2) and by synthetic estrogen receptor-selective ligands such as diarylpropionitrile (DPN) and can reportedly be modulated in part by breast cancer therapies such as toremifene, tamoxifen, and raloxifen. IGF-2 signaling may also promote acute phosphorylation of ERβ and late induction of ERβ transcription. Metformin, a common therapeutic used to manage diabetes mellitus type 2, has been demonstrated to be effective in partial suppression of TNBC by activating AMPK (which in turn inhibits mTOR downstream signaling) and/or by suppressing systemic insulin-like growth factor levels in vivo. Arrows represent a pathway of activation and solid lines represent inhibition. See text for details.
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