Abstract
About 50-70% of breast cancers are estrogen receptor α (ERα) positive and most of them are sensitive to endocrine therapy including tamoxifen. However, one third of these patients will eventually develop resistance and relapse. We found that the expression of miR-15a and miR-16 were significantly decreased in tamoxifen resistant ER positive breast cancer cell lines. Exogenous expression of miR-15a/16 mimics re-sensitized resistant cells to tamoxifen by inhibiting Cyclin E1 and B cell lymphoma-2 (Bcl-2) to induce cell growth arrest and apoptosis respectively. Further, we identified that a repressive member of E2F family, E2F7, was responsible for the suppression of miR-15a/16 cluster by competing with E2F1 for E2F binding site at the promoter of their host gene DLEU2. Moreover, high expression of E2F7 is correlated with high risk of relapse and poor prognosis in breast cancer patients receiving tamoxifen treatment. Together, our results suggest that overexpression of E2F7 represses miR-15a/16 and then increases Cyclin E1 and Bcl-2 that result in tamoxifen resistance. E2F7 may be a valuable prognostic marker and a therapeutic target of tamoxifen resistance in breast cancer.
Highlights
Oestrogen signaling plays a central role in female physiology through its effects on critical cellular processes, including cell proliferation and survival
estrogen receptor α (ERα) positive and tamoxifen sensitive breast cancer cell lines MCF7 and T47D were cultured in phenol-free media supplied with charcoal-stripped bovine serum and exposed to increased concentration of tamoxifen up to 1 μM for 1 year
Our further investigation indicated that most of miR-15a family members, especially miR-15a/16, were reduced in the MCF7-Re cells and exogenous overexpression of miR15a/16 re-sensitized MCF7-Re and T47D-Re cells to tamoxifen by inducing cell cycle arrest and apoptosis
Summary
Oestrogen signaling plays a central role in female physiology through its effects on critical cellular processes, including cell proliferation and survival. About 50-70% of breast cancer patients are classified as ERα positive and interference with ERα signaling has been an effective treatment strategy for over a century [1]. Tamoxifen has been the most widely used endocrine therapy in ERα positive breast cancer patients for more than 30 years [2]. Various mechanisms have been proposed to explain tamoxifen resistance, including loss of ERα expression [3] and cross-talk between ER and receptor tyrosine kinase signaling [4, 5]. Recent studies reported that abnormal expression of miRNAs plays a role in tamoxifen resistance. The mechanism is unclear and whether miR-15a/16 have a role in the tamoxifen resistance of HER2-negative ERα-positive cancers remains unknown
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