Identification of the Mechanisms Underlying Antiestrogen Resistance: Breast Cancer Research Partnership between FIU-UM Braman Family Breast Cancer Institute.

摘要

We have completed all proposed training and research project tasks. This research proposal had two primary objectives which were to (1) increase FIU investigators research expertise and competitive ability to succeed as independent breast cancer researchers; and (2) to execute research with the promise of identifying molecular causes of breast tumor resistance to antiestrogen therapy. We observed in this study that antiestrogen resistant cell lines LCC-2 and LY-2 regained sensitivity to the growth inhibitory effects of antiestrogens Tamoxifen and Fulvestrant by treatment with ROS modulators and and in vivo growth of LCC-2 was inhibited by ROS modulators. Overexpression of ROS modifiers in the tamoxifen resistant breast cancer cell line LCC2 appears to restore sensitivity to growth inhibition by Tamoxifen through activating AKT phosphorylation. Regained antiestrogen sensitivity of LCC2 to tamoxifen seems to be partly mediated by redox sensitive phosphorylation of p27 at Ser-10, Thr- 187, and Thr-157. ROS modifiers presumably restore the growth inhibitory effects of antiestrogen in resistant cells through regulating phosphorylation of p27 and interaction of p27 with Cdk2 and cyclin E. Our findings show support towards our hypothesis, with increased ROS and cell proliferation in breast cancer cells upon treatment with antiestrogen Tamoxifen, and the cotreatment with ebselen or overexpression of catalase may restore the growth inhibitory effects of Tamoxifen in resistant cells.