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

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.

Repeated Exposure to 4-Methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP), an Active Metabolite of Bisphenol A, Aggressively Stimulates Breast Cancer Cell Growth in an Estrogen Receptor β (ERβ)–Dependent Manner

“…In the case of BPA, it has been reported that under in vivo conditions, BPA is readily converted to BPA-glucuronide (via phase II reaction); however, BPAglucuronide has itself also been proven to be a possible active metabolite that induces adipogenesis in human and murine preadipocytes (Boucher et al, 2015). Although it has been suggested that ERb has a possible protective role against breast tumor progression, the accumulated evidence suggests that ERb also acts as a mediator of estrogen action, coupled with tumorigenesis, in breast cancer cells, and that its expression is remarkably upregulated in tamoxifen-resistant breast cancers (Dotzlaw et al, 1999;Speirs et al, 1999a,b;Power and Thompson, 2003;Hamilton et al, 2015;Ma et al, 2017). Collectively, including our findings here, it is suggested that the negative biologic effects of BPA are exerted through several Fig.…”

“…Furthermore, it has been suggested that ERb may be a tumor suppressor owing to its reduced expression during cancer development (Iwao et al, 2000). However, the accumulated evidence suggests that ERb also acts as a mediator of estrogen action in breast cancer cells (Speirs et al, 1999a;Hamilton et al, 2015;Ma et al, 2017). Thus, in the present study, we investigated the effects of repeated exposure to BPA, together with MBP, at concentrations similar to environmental levels on the expression of ERa/b, and investigated the ER subtype that was involved in these effects.…”

Extranuclear signaling by sex steroid receptors and clinical implications in breast cancer

“…In addition, conformation of E2 binding of plasma membrane proteins was established through ERα knockout models in astrocytes [69]. Although ERs localize predominantly in tumor cell nuclei, a significant pool of ERs has been shown to localize in extranuclear sites in archival BC and NSCLC cells [41, 66, 70, 71]. Thus, important actions initiated by membrane-associated forms of ER may play a collaborative role with liganded-ERs in the nucleus to promote signaling for hormone-mediated proliferation and survival of BCs.…”

“…ERβ forms occur in tumor cell nuclei, but also at extranuclear sites [71, 264]. ERβ can activate transcription by nuclear or indirectly by extranuclear pathways by interaction with coactivators/co-regulators such as PELP1 and SRAP [265] that in turn modulate signaling cascades to impact gene expression and TNBC progression [70, 71, 264, 266, 267]. As a consequence of such preclinical work, clinical studies to target ERβ are being planned in patients afflicted with metastatic TNBC [268].…”

Carcinogenesis of Triple-Negative Breast Cancer and Sex Steroid Hormones

“…Products of primary responsive genes further promote the transcription of secondary or tertiary responsive genes, finally resulting in a dynamic action. These signal pathways crosstalk with the other signal transduction pathways through growth factor receptors or various membrane-bound receptors ( Figure 3 ) [ 12 , 63 , 64 ].…”