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ERR Mediates Tamoxifen Resistance in Novel Models of Invasive Lobular Breast Cancer

¹ Lombardi Comprehensive Cancer Center and Department of Oncology, Georgetown University School of Medicine, Washington, District of Columbia; ² Department of Electrical and Computer Engineering, Virginia Polytechnic Institute and State University, Arlington, Virginia; and ³ Barbara Ann Karmanos Cancer Institute and Department of Pathology, Wayne State University, Detroit, Michigan

Requests for reprints: Rebecca B. Riggins, Room E407 Research Building, Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, 3970 Reservoir Road Northwest, Washington, DC 20057. Phone: 202-687-7451; Fax: 202-687-7505; E-mail: rbr7{at}georgetown.edu.

Key Words: ER • ERR • breast cancer • ILC • endocrine resistance

One-third of all estrogen receptor (ER)–positive breast tumors treated with endocrine therapy fail to respond, and the remainder is likely to relapse in the future. Almost all data on endocrine resistance has been obtained in models of invasive ductal carcinoma (IDC). However, invasive lobular carcinomas (ILC) comprise up to 15% of newly diagnosed invasive breast cancers each year and, whereas the incidence of IDC has remained relatively constant during the last 20 years, the prevalence of ILC continues to increase among postmenopausal women. We report a new model of Tamoxifen (TAM)-resistant invasive lobular breast carcinoma cells that provides novel insights into the molecular mechanisms of endocrine resistance. SUM44 cells express ER and are sensitive to the growth inhibitory effects of antiestrogens. Selection for resistance to 4-hydroxytamoxifen led to the development of the SUM44/LCCTam cell line, which exhibits decreased expression of ER and increased expression of the estrogen-related receptor (ERR). Knockdown of ERR in SUM44/LCCTam cells by siRNA restores TAM sensitivity, and overexpression of ERR blocks the growth-inhibitory effects of TAM in SUM44 and MDA-MB-134 VI lobular breast cancer cells. ERR-driven transcription is also increased in SUM44/LCCTam, and inhibition of activator protein 1 (AP1) can restore or enhance TAM sensitivity. These data support a role for ERR/AP1 signaling in the development of TAM resistance and suggest that expression of ERR may be a marker of poor TAM response. [Cancer Res 2008;68(21):8908–17]

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				Correction: Article on Endocrine Resistance in Lobular Carcinoma Cancer Res., February 15, 2009; 69(4): 1695 - 1695. [Full Text] [PDF]