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

[摘要] 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 andprogesterone receptors and HER-2 overexpression and cannot be treatedwith 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 ERαmay be such a target. Using human TNBC specimens with known clinical outcomes to assess ERβexpression, we find that ERβ1 associates with significantly worse 5-year overall survival. Further, a panel of TNBC cell lines exhibit significant levels of ERβprotein. To assess ERβeffects on proliferation, ERβexpression 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 ERβmay 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 ERβmRNA in TNBC cells. This work may help elucidate the interplay of metabolic and growth factors in TNBC.

[学科分类] 基础医学