Abstract
BackgroundTumor resistance to the selective estrogen receptor modulator tamoxifen remains a serious clinical problem especially in patients with tumors that also overexpress HER2. We have recently demonstrated that the clinically important isoform of HER2, HERΔ16, promotes therapeutically refractory breast cancer including resistance to endocrine therapy. Likewise additional breast tumor cell models of tamoxifen resistance have been developed that do not involve HER2 overexpression. However, a unifying molecular mechanism of tamoxifen resistance has remained elusive.ResultsHere we analyzed multiple cell models of tamoxifen resistance derived from MCF-7 cells to examine the influence of microRNAs (miRNAs) on tamoxifen resistance. We compared miRNA expression profiles of tamoxifen sensitive MCF-7 cells and tamoxifen resistant MCF-7/HER2Δ16 cells. We observed significant and dramatic downregulation of miR-342 in the MCF-7/HER2Δ16 cell line as well as the HER2 negative but tamoxifen resistant MCF-7 variants TAMR1 and LCC2. Restoring miR-342 expression in the MCF-7/HER2Δ16 and TAMR1 cell lines sensitized these cells to tamoxifen-induced apoptosis with a dramatic reduction in cell growth. Expression of miR-342 was also reduced in a panel of tamoxifen refractory human breast tumors, underscoring the potential clinical importance of miR-342 downregulation. Towards the goal of identifying direct and indirect targets of miR-342 we restored miR-342 expression in MCF-7/HER2Δ16 cells and analyzed changes in global gene expression by microarray. The impact of miR-342 on gene expression in MCF-7/HER2Δ16 cells was not limited to miR-342 in silica predicted targets. Ingenuity Pathways Analysis of the dataset revealed a significant influence of miR-342 on multiple tumor cell cycle regulators.ConclusionsOur findings suggest that miR-342 regulates tamoxifen response in breast tumor cell lines and our clinical data indicates a trend towards reduced miR-342 expression and tamoxifen resistance. In addition, our results suggest that miR-342 regulates expression of genes involved in tamoxifen mediated tumor cell apoptosis and cell cycle progression. Restoring miR-342 expression may represent a novel therapeutic approach to sensitizing and suppressing the growth of tamoxifen refractory breast tumors.
Highlights
Tumor resistance to the selective estrogen receptor modulator tamoxifen remains a serious clinical problem especially in patients with tumors that overexpress HER2
Cell Lines Human mammary carcinoma cell line MCF-7 was purchased from the American Type Culture Collection (Manassas, VA) and maintained in MEM supplemented with 10% fetal bovine serum (FBS)
Results miR-342 Expression is Suppressed in Tamoxifen Resistant Breast Tumor Cells We have recently shown that ectopic expression of HER2Δ16, but not wild-type HER2 promotes tamoxifen resistance and estrogen independence of ERa positive MCF-7 cells in part through modulation of miR-15a/16 [12,15]
Summary
Tumor resistance to the selective estrogen receptor modulator tamoxifen remains a serious clinical problem especially in patients with tumors that overexpress HER2. We have recently demonstrated that the clinically important isoform of HER2, HERΔ16, promotes therapeutically refractory breast cancer including resistance to endocrine therapy. 70% of breast cancer patients develop tumors expressing the estrogen receptor (ERa) and are candidates for endocrine therapy. The selective ERa modulator tamoxifen, is the most commonly prescribed endocrine therapy, but 30-40% of patients fail adjuvant tamoxifen therapy and most patients with metastatic disease develop tamoxifen resistance [1]. Half of the ERa positive tumors express HER2 and over 70% of these patients may exhibit de novo tamoxifen resistance [6,7]. A large percentage of HER2/ERa positive tumors acquire estrogen-independence and continue to grow when patients are estrogen depleted [6]
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