Estrogen is a potent mitogen that stimulates cell proliferation and prevents cell death in breast cancer cells through activation of the ER. Paradoxically, estrogen is also capable of inducing tumor regression of hormone-dependent breast cancer in postmenopausal women who have been treated exhaustively with anti-hormones. Preclinical studies suggest that the evolution of anti-hormone resistance over years of therapy reconfigures the survival mechanism of the breast cancer cell so that estrogen no longer functions as a survival factor but as a death signal. One of the goals of my lab is to determine the mechanism(s) by which estrogens (i.e. 17β-estradiol and related compounds) induce apoptosis in breast cancer cells that have acquired resistance to antihormones.

My laboratory is also investigating whether oxidative stress is capable of modifying the responsiveness of breast cancer cells to various antihormones. We are specifically focusing on the impact of elevated glutathione levels and its role in antihormone resistance. We have previously developed a LTED breast cancer cell line called MCF-7:2A, which is resistant to estrogen deprivation and it does not undergo estradiol-induced apoptosis like other LTED breast cancer cells. We have found that these cells possess elevated levels of glutathione (GSH) and they overexpress the genes involved in GSH synthesis. Interestingly, depletion of glutathione levels in MCF-7:2A cells using buthionine sulfoximine (BSO), a potent inhibitor of glutathione (GSH) synthesis, is capable of sensitizing these cells to estradiol induced apoptosis. BSO, either alone or in combination with estradiol, also causes tumor regression of MCF-7:2A cells in vivo.

Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) is a glycosylphosphatidylinositol-anchored cell surface protein that functions as a homotypic intercellular adhesion molecule. It is overexpressed in a number of human malignancies including pancreatic cancer, gastrointestinal cancer, and breast cancers and increased levels of CEACAM6 are inversely correlated to the differentiation state of cancer cells. Previous studies have shown that CEACAM6 is overexpressed in pancreatic adenocarcinoma cells and its overexpression is associated with greater in vivo metastatic ability and increased invasiveness and migration. More recently, Poola and coworkers reported that the expression of CEACAM6 was associated with the development of invasive breast cancer (IBC). More recently, our laboratory has found that CEACAM6 is overexpressed in LTED breast cancer cell lines; MCF-7:5C and MCF-7:2A, and its overexpression is associated with a more aggressive invasive phenotype in vitro. Furthermore, we found that suppression of CEACAM6 expression using small interfering RNA (siRNA) completely reversed the migratory and invasive ability of MCF-7:5C and MCF-7:2A cells and it significantly reduced E-cadherin, Akt, and expression in these cells. Our goal is to further characterize the role of CEACAM6 in LTED breast cancer cells and determine whether CEACAM6 is also overexpressed in other antihormone-resistant breast cancer cell models.

My laboratory is also studying the role of a new selective estrogen receptor modulator (SERM) bazedoxifene, that is currently in clinical trial for the prevention of osteoporosis and breast cancer. We are conducting an evaluation of the effect of this SERM and other SERMs on the regulation of estrogen receptor turnover. Interestingly, we have found that bazedoxifene actually is cytotoxic for breast cancer cells at concentrations that could be achieved clinically.