Abstract
Background We aimed to elucidate the molecular mechanisms of tamoxifen resistance in breast cancer. Methods We did gene array analyses and identified 366 genes with altered expression in four unique tamoxifen-resistant cell lines versus the parental tamoxifen-sensitive MCF-7/S0.5 cell line. Most of these genes were functionally linked to cell proliferation, death, and control of gene expression, and include FYN, PRKCA, ITPR1, DPYD, DACH1, LYN, GBP1, and PRLR. We also evaluated the subcellular localisation of FYN in primary breast tumours from two cohorts of endocrine-treated ER+ breast cancer patients, one with advanced disease (n = 47) and the other with early disease (n = 76). Findings Treatment with FYN-specific small interfering RNA or a SRC family kinase inhibitor reduced cell growth of tamoxifen-resistant cell lines, while exerting no significant effect on MCF-7/S0.5 cells. Moreover, overexpression of FYN in parental tamoxifen-sensitive MCF-7/S0.5 cells resulted in reduced sensitivity to tamoxifen treatment, while knockdown of FYN in the FYN-overexpressing MCF-7/S0.5 cells restored sensitivity to tamoxifen, demonstrating growth-promoting and survival-promoting function of FYN in MCF-7 cells. FYN knockdown in tamoxifen-resistant cells led to reduced phosphorylation of 14-3-3 and Cdc25A, suggesting that FYN, by activation of important cell cycle-associated proteins, could overcome the antiproliferative effects of tamoxifen. Evaluation of the subcellular localisation of FYN in breast cancer patients showed that in those with advanced disease, plasma membrane-associated FYN expression strongly correlated with longer progression-free survival (p Interpretation Our results indicate that FYN plays an important part in tamoxifen resistance, and its subcellular localisation in breast tumour cells could be an important novel biomarker of response to endocrine therapy in breast cancer.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
