Amphiregulin is a critical downstream effector of estrogen signaling in ERAlpha-positive breast cancer

Estrogen stimulation promotes epithelial cell proliferation in estrogen receptor (ERAlpha)-positive breast cancer. Many ERAlpha target genes have been enumerated, but the identities of the key effectors mediating the estrogen signal remain obscure. During mouse mammary gland development, the EGF eceptor ligand amphiregulin acts as an important stage-specific effector of estrogen signaling. In this study, we investigated the role of amphiregulin in breast cancer cell proliferation using human tissue samples and tumor xenografts in mice. Amphiregulin was enriched in ERAlpha-positive human breast tumor cells and required for estrogen-dependent growth of MCF7 tumor xenografts. Further, amphiregulin levels were suppressed in patients treated with endocrine therapy. Suppression of EGF receptor signaling appeared necessary for the amphiregulin response in this setting. Our findings implicate amphiregulin as a critical mediator of the estrogen response in ERAlpha-positive breast cancer, emphasizing the importance of EGF receptor signaling in breast tumor pathogenesis and therapeutic response.

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