Biologic Roles of Estrogen Receptor-β and Insulin-Like Growth Factor-2 in Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) occurs in 10-15% of patients yet accounts for almost half of all breast cancer deaths. TNBCs lack expression of estrogen and progesterone receptors and HER-2 overexpression and cannot be treated with current targeted therapies. TNBCs often occur in African American and younger women. Although initially responsive to some chemotherapies, TNBCs tend to relapse and metastasize. Thus, it is critical to find new therapeutic targets. A second ER gene product, termed ERβ, in the absence of ERα may be such a target. Using human TNBC specimens with known clinical outcomes to assess ERβ expression, we find that ERβ1 associates with significantly worse 5-year overall survival. Further, a panel of TNBC cell lines exhibit significant levels of ERβ protein. To assess ERβ effects on proliferation, ERβ expression in TNBC cells was silenced using shRNA, resulting in a significant reduction in TNBC proliferation. ERβ-specific antagonists similarly suppressed TNBC growth. Growth-stimulating effects of ERβ may be due in part to downstream actions that promote VEGF, amphiregulin, and Wnt-10b secretion, other factors associated with tumor promotion. In vivo, insulin-like growth factor-2 (IGF-2), along with ERβ1, is significantly expressed in TNBC and stimulates high ERβ mRNA in TNBC cells. This work may help elucidate the interplay of metabolic and growth factors in TNBC.