Abstract 5046: Amphiregulin is a key effector of estrogen receptor in breast cancer
Authors: Esther A. Peterson, Natasha Chandiramani, Evelyn J. Aranda Jaque, E. Charles Jenkins, Paraic A. Kenny
Journal: Cancer Research (2015)

Abstract Estrogen is an essential hormone for mammary gland development and is a key driver of proliferation during the development of estrogen receptor positive breast tumors. The actions of estrogen are primarily mediated by its receptor, the ERα transcription factor, which regulates several hundred estrogen-responsive genes in breast cancer cells. However, despite much investigation, the identity of the key effectors of this proliferative signal in breast cancer remains unclear. Amphiregulin (AREG) is a ligand of the Epidermal Growth Factor Receptor. It is transcriptionally regulated by estrogen and is required for estrogen-dependent mouse mammary gland development. In this study, we have tested whether Amphiregulin is a key effector of estrogen in breast cancer. shRNA-mediated knockdown of Amphiregulin in MCF7 cells strongly attenuated ER+ breast cancer cell line growth in vivo. Conversely, expression of Amphiregulin from an estrogen-insensitive promoter allowed MCF7 xenografts to escape the therapeutic effects of tamoxifen. Thus, Amphiregulin expression is both necessary and sufficient for the proliferative response to estrogen in MCF7 cells in vivo, and downregulation of Amphiregulin in response to tamoxifen is required for a therapeutic benefit. After initially responding to endocrine therapy, many ER+ tumors progress to resistance to these therapies. Our model predicts that breast tumors which either (1) express AREG in an estrogen-insensitive manner or (2) have elevated levels of alterative ERBB family ligands, will be endocrine resistant. We present experimental and clinical evidence demonstrating that these features contribute to at least some examples of endocrine resistance. Firstly, in MCF7 cells selected for resistance to fulvestrant, we show that AREG expression is no longer regulated by estrogen or its antagonists, but the cells remain AREG-dependent. Secondly, in a series of 52 ER+ breast cancer patients treated with neo-adjuvant letrozole, we show that the downregulation of Amphiregulin in response to endocrine therapy observed in our mouse studies is recapitulated in human breast cancer patients, and that tumors in which alternate ERBB ligands (TGFalpha, Epiregulin, and Neuregulins 1 &amp; 2) are expressed at high levels are least likely to respond to letrozole. In summary, these data underline the importance of ERBB signaling in estrogen receptor positive breast cancer and implicate Amphiregulin as the primary ERBB ligand in mediating the effects of estrogen in these tumors. Citation Format: Esther A. Peterson, Natasha Chandiramani, Evelyn J. Aranda Jaque, E. Charles Jenkins, Paraic A. Kenny. Amphiregulin is a key effector of estrogen receptor in breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5046. doi:10.1158/1538-7445.AM2015-5046