TGFα-EGFR pathway in breast carcinogenesis, association with WWOX expression and estrogen activation.

WWOX is a tumor-suppressive steroid dehydrogenase, which relationship with hormone receptors was shown both in animal models and breast cancer patients. Herein, through nAnT-iCAGE high-throughput gene expression profiling, we studied the interplay of estrogen receptors and the WWOX in breast cancer cell lines (MCF7, T47D, MDA-MB-231, BT20) under estrogen stimulation and either introduction of the WWOX gene by retroviral transfection (MDA-MB-231, T47D) or silenced with shRNA (MCF7, BT20). Additionally, we evaluated the consequent biological characteristics by proliferation, apoptosis, invasion, and adhesion assays. TGFα-EGFR signaling was found to be significantly affected in all examined breast cancer cell lines in response to estrogen and strongly associated with the level of WWOX expression, especially in ER-positive MCF7 cells. Under the influence of 17β-estradiol presence, biological characteristics of the cell lines were also delineated. The study revealed modulation of adhesion, invasion, and apoptosis. The obtained results point at a complex role of the WWOX gene in the carcinogenesis of the breast tissue, which seems to be closely related to the presence of estrogen α and/or β receptors.