Abstract
Triple negative breast cancer (TNBC) is characterized by lack of expression of the estrogen and progesterone receptors and HER2, which are common therapeutic targets. CDK4/6 inhibitor Palbociclib has been approved as an anti-cancer agent for breast cancer. However, identifying biomarkers that predict the response to Palbociclib has always been a challenge for molecular targeted therapy. In this study, we identify microRNA as a hallmark in TNBC patients and explore if miR-3613-3p might serve as a tumor suppressor biomarker for triple negative breast cancer patients and if overexpression of miR-3613-3p could enhance the sensitivity of TNBC cells to Palbociclib. We show that the expression of miR3613-3p was down-regulated in TNBC tumors and cells, and the overexpression of miR-3613-3p in patients’ tumor tissues was clinically and pathologically correlated with favorable prognosis, such as smaller tumor size and the lower Ki-67. In vitro, overexpression of miR-3613-3p inhibited cell proliferation, induced G1 cell-cycle arrest, and enhanced the sensitivity of TNBC cells to Palbociclib treatment. In vivo study revealed that overexpression of miR-3613-3p inhibited TNBC tumorigenesis and exerted a significant inhibitory effect of Palbociclib on MDA-MB-231 cells. Mechanically, SMAD2 and EZH2 were found to be two direct targets of miR-3613-3p and mediate the proliferation of TNBC cells and the sensitivity of the cells to Palbociclib through inducing cellular senescence. Our findings suggested that miR-3613-3p acts as a cancer-suppressor miRNA in TNBC. Moreover, our study showed that miR-3613-3p might be used as a predictive biomarker for the response of TNBC to Palbociclib.
Highlights
Breast cancer remains the most common cancer and the second leading cause of cancer death in women, after lung cancer [1] and is the primary cause of cancer deaths in women [2]
We first examined the expression of miR-3613-3p in 44 paired breast cancer tissues by qRT-polymerase chain reaction (PCR)
To investigate whether miR-3613-3p regulates the growth of triple negative breast cancer (TNBC) cells and enhances their sensitivity to Palbociclib via the targets we identified, we first performed cell viability assay to assess the roles of the targets in cell proliferation
Summary
Breast cancer remains the most common cancer and the second leading cause of cancer death in women, after lung cancer [1] and is the primary cause of cancer deaths in women [2]. Breast cancer represents a heterogeneous disease with distinct biological subtypes [3]. The triple negative breast cancer (TNBC) neither expresses the two hormone receptors nor expresses HER2 and its presence is associated with the worst prognostic outcome [4]. Unlike other breast tumor subtypes, it doesn’t express readily detectable receptors; anti-tumor agents targeting TNBC have not yet been available [6]. Many researchers are looking for specific targeted drugs to treat TNBC [7], but no significant progress has been made so far
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