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(American Journal of Pathology. 2007;170:1546-1560.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.061004

Direct Involvement of Breast Tumor Fibroblasts in the Modulation of Tamoxifen Sensitivity

Malathy P.V. Shekhar*{dagger}, Steven Santner*, Kathryn A. Carolin*{ddagger} and Larry Tait*

From the Breast Cancer Program,* Karmanos Cancer Institute, and the Departments of Pathology{dagger} and Surgery,{ddagger} Wayne State University School of Medicine, Detroit, Michigan

Using contact-dependent three-dimensional coculture systems and serum-free conditions, we compared the ability of estrogen receptor (ER)-{alpha}+ tamoxifen-sensitive premalignant (EIII8) or tumorigenic (MCF-7), ER-{alpha}+ tamoxifen-resistant (EIII8-TAMR) or ER-{alpha}– MDA-MB-231 breast cancer cells to interact and undergo epithelial morphogenesis on association with breast tumor-derived fibroblasts. Although all breast cancer cell lines interacted with tumor fibroblasts, EIII8 and its intrinsically tamoxifen-resistant counterpart EIII8-TAMR cells were most receptive and responded with dramatic, albeit, aberrant epithelial morphogenesis. EIII8 cells underwent epithelial morphogenesis when cocultured with fibroblasts from ER-{alpha}–/PgR– or ER-{alpha}+/PgR+ breast tumors; however, EIII8 cells cocultured with ER-{alpha}–/PgR– tumor-derived fibroblasts exhibited decreased tamoxifen sensitivity compared with cells cocultured with ER-{alpha}+/PgR+ tumor fibroblasts. Fibroblast-induced tamoxifen resistance was accompanied by mitogen-activated protein kinase and Akt hyperactivation, reduced sensitivity to U0126 or LY294002, and ER-{alpha} hyperphosphorylation in the activation function-1 domain. The intrinsic tamoxifen resistance of EIII8-TamR cells correlated with constitutive ER-{alpha} hyperphosphorylation that was unaffected by the tumor fibroblasts. Our results suggest that tumor fibroblast-induced tamoxifen resistance of EIII8 cells is not mediated by epidermal growth factor receptor or insulin-like growth factor (IGF)-1R axes because no correlation was found between expression levels of IGF-1, IGF-2, phosphorylated IGF-1R, or epidermal growth factor receptor, and tamoxifen sensitivity of EIII8 fibroblast cultures.




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