Estrogen Signaling in ERα-Negative Breast Cancer: ERβ and GPER

Estrogen receptors are important regulators of the growth of breast tumors. Three different receptors for estrogens have been identified in breast tumors, two nuclear receptors, ERa and ERb, and a G-protein coupled estrogen receptor 1 (GPER) that initiates non-genomic effects of estrogens in the cytosol. Recent findings show that the stimulation of cytoplasmic ERa and ERb also triggers non-genomic signaling pathways. The treatment of breast cancer with anti-estrogens depends on the presence of ERa. About 40% of all breast cancers, however, do not express ERa. One subgroup of these tumors overexpress Her-2, another important group is designated as triple-negative breast cancer, as they neither express ERa, nor progesterone receptors, nor do they overexpress Her-2. This review addresses the signaling of ERb and GPER in ERa-negative breast tumors. In addition to the well-established EGF-receptor transactivation pathways of GPER, more recent findings of GPER-dependent activation of FOXO3a, the Hippo-pathway, and HOTAIR-activation are summarized.