[Proc Amer Assoc Cancer Res, Volume 47, 2006]
Endocrinology 3: Hormone Signaling in Breast Cancer
Deregulation of ER, ERR, and estrogen-regulated genes accompany endocrine resistance in a model of invasive lobular breast carcinoma
Rebecca B. Riggins,
Bassem R. Haddad,
Stephen P. Ethier and
Georgetown University, Washington, DC and Barbara Ann Karmanos Cancer Institute, Detroit, MI
Invasive lobular carcinoma (ILC) is a histologic subtype that comprises 2-15% of all breast cancers; 47-79% are the more common invasive ductal carcinoma (IDC). Interestingly, a significantly higher percentage of ILC tumors are robustly estrogen receptor-positive (ER+) and progesterone receptor-positive (PR+). Antiestrogens such as the nonsteroidal triphenylethylene Tamoxifen (Tam), the steroidal pure antagonist Fulvestrant (ICI 182,780), and aromatase inhibitors are the primary therapeutic agents of choice for women whose tumors are ER+. Unfortunately, endocrine resistance is a significant clinical problem; one third of women treated with Tam do not respond, and the remaining 70% are likely to relapse in the future. It is critically important to define the mechanisms of endocrine therapy response and resistance in order to improve the efficacy of antiestrogens and aromatase inhibitors and to enhance our understanding of breast cancer as a whole. However, current in vitro and xenograft models of endocrine resistance are based upon cell lines derived from IDC tumors. We sought to develop a new model of endocrine resistance that may better represent the ILC subtype. The SUM44 breast cancer cell line was derived from an ILC metastasis, is ER+/PR+, and displays other classic features of ILC such as loss of E-cadherin and no amplification of ErbB2. We found that despite being ER+, SUM44 cells are completely unresponsive to estrogen-induced proliferation, which may be explained by the finding that these cells also express 3-fold higher levels of the CYP19A1 aromatase gene when compared with the estrogen-dependent MCF-7 cell line. However, SUM44 cells are significantly growth inhibited by both Tam and ICI 182,780. SUM44 cells were then selected against increasing concentrations of Tam, resulting in the establishment of the resistant subline LCCTam. LCCTam cells also display cross-resistance to ICI 182,780, whereas most other Tam-resistant breast cancer models retain sensitivity to steroidal antiestrogens. By gene expression microarray analysis, >1100 genes were differentially expressed between the two cell lines. ER and several estrogen-regulated genes such as TFF1/pS2 were significantly downregulated in LCCTam cells, while the estrogen-related receptor gamma (ERR) was significantly upregulated. Because SUM44 and LCCTam are the only cell line models for endocrine resistance in ILC, we wanted to address how relevant they may be as a model for human ILC tumors. Therefore, we compared the gene expression patterns of SUM44 cells to 10 ER+/PR+ ILC tumor samples, and found a nearly 80% overlap in the panel of expressed genes between the two groups. Altogether, our findings suggest that SUM44 is a good model for ILC and that endocrine resistance in this breast cancer subtype is likely due to changes in hormone receptor signaling.
Copyright © 2006 by the American Association for Cancer Research.