Endocrine therapies that target estrogen and ER signaling pathways play a critical role in the treatment of the majority of breast cancer patients. However, over a quarter of breast tumors fail to express ER and are thus resistant to these therapies. Our findings suggest that there are a significant number of ER−/HER2+ breast tumors that express AR and are growth stimulated by androgens. We have shown that androgens and AR stimulate oncogenic Wnt and HER2 signaling pathways by transcriptional upregulation of WNT7B and HER3 in ER−/HER2+ breast cancer (as summarized in ), by which androgen stimulates tumor cell growth. This regulatory network indicates an intrinsic link between AR and growth factor pathways in ER-negative breast cancer.
Hormonal regulation of Wnt expression has been suggested in mammary gland development, such as WNT4 by progesterone (Brisken et al., 2000
), and WNT5B and WNT7B by human chorionic gonadotropin (hCG) (Kuorelahti et al., 2007
), whereas the direct effect of androgen and AR on WNT
expression was previously unknown in the normal mammary gland or breast tumors. Overexpression of Wnts causes aberrant activation of the Wnt signaling pathway, which is a major driving force in a broad spectrum of human cancers. In this study, we have shown that AR-stimulated elevation of WNT7B leads to activated nuclear translocation of β-catenin. This in turn leads to β-catenin interaction with AR to induce HER3
gene expression. These findings highlight a crucial androgen-dependent signaling cascade that is regulated by AR in ER−/HER2+ breast cancer. The nuclear localization of β-catenin is an important predictor of poor prognosis and outcome in colorectal cancer. However, the subcellular location of β-catenin has not been well investigated in breast cancer. We find that the collaboration between β-catenin and AR together with FOXA1 plays an important role in ER−/HER2+ breast tumors through binding to regulatory regions of the HER3
is receiving increased attention as a therapeutic target in HER2+ breast cancers. Clinical studies of EGFR and HER2 antagonists suggest that HER2+ breast cancer is primarily driven by HER2/HER3 heterodimers rather than HER2/EGFR heterodimers (reviewed in (Baselga and Swain, 2009
)). Interfering with HER2/HER3 heterodimerization has been suggested as an option to inhibit HER3 activation with the development of agents such as pertuzumab. Our work indicates that targeting AR with antagonists such as bicalutamide, may be another way to target HER3. Clinical trials of the anti-androgen bicalutamide in ER−/AR+ metastatic breast cancer are ongoing (NCT00468715). Our study also suggests that pharmacological inhibitors targeting AR-regulated pathways will only be effective in the presence of active androgen signaling and may be limited to ER−/HER2+ tumors. Expression of androgen/AR-regulated genes in ER−/HER2+ breast tumors could be predictors of a therapeutic response to AR target therapies. It has been shown that the signaling pathways including Wnt, HER2 and PI3K/AKT are able to actively enforce AR activity, constituting positive feed-forward circuits (Mellinghoff et al., 2004
; Mulholland et al., 2006
; Terry et al., 2006
). This may potentially lead to androgen-independent AR activation in breast tumors, as has been demonstrated in castration-resistant prostate cancer (Wang et al., 2009
). Collectively, this work provides not only novel insights into androgen-dependent AR function in breast cancer, but also reveals the mechanistic basis for targeting AR as a therapeutic opportunity for patients with invasive ER−/HER2+ breast tumors.