Abstract A47: MicroRNA-510 as a predictive marker for response to platinum-based chemotherapy in triple negative breast cancer
Authors: Qi Jin Guo, Jamie N. Miils, Natalie Mason, Savannah G. Bandurraga, Lourdes M. Nogueira, Rita Kramer, David P. Turner, Victoria J. Findlay
Journal: Clinical Cancer Research (2015)

Abstract Breast cancer is a heterogeneous disease with multiple subtypes, which are clinically classified based on the expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). Associated with the poorest prognosis of all subtypes, triple negative breast cancer (TNBC) is defined as ER-/PR-/HER2-; without these molecular targets, these cancers are insensitive to highly effective targeted therapies and systemic chemotherapy remains the mainstay of treatment for these women. Resent research has shown that platinum chemotherapy agents are particularly active in TNBC, including a clinical trial that demonstrated single agent cisplatin alone can induce response in a subset of TNBC patients. The identification of biomarkers to predict response is required to distinguish patients most likely to benefit from this agent from resistant ones, whom may respond better from other forms of chemotherapy. We have published studies examining the role of miR-510 in breast cancer and observed that miR-510 expression is elevated in tumors when compared to matched non-tumor samples. Drug cytotoxicity assays indicate miR-510 positively correlates with sensitivity to cisplatin in vitro. Furthermore, inhibition of miR-510 causes sensitive breast cancer cell lines to be more resistant in vitro, while overexpression of miR-510 restores sensitivity to cisplatin in resistant breast cancer cell lines both in vitro and in vivo. Recent mechanistic studies have revealed that cisplatin activates the ΔNp63/TAp73 apoptotic pathway specifically in in TNBC with p53 mutations (∼60% of all TNBCs). We have validated peroxiredoxin 1 (Prdx1) as a direct target of miR-510 and studies have also indicated that Prdx1 is a negative regulator of the ΔNp63/Tap73 pathway, suggesting that miR-510 may mediate sensitivity to cisplatin through the negative regulation of Prdx1. We demonstrate an increase in the activation of this pathway in TNBC cells expressing miR-510 upon cisplatin treatment. Based on these data we propose that elevated levels of miR-510 mediates cisplatin sensitivity and that it may serve as a non-invasive biomarker to predict response to cisplatin in TNBC patients. To this end, we have shown by qPCR that miR-510 levels are detectable in serum samples from a subset of human breast cancer patients, and further studies will assess positive correlations between miR-510 expression and cisplatin sensitivity. Citation Format: Qi Jin Guo, Jamie N. Miils, Natalie Mason, Savannah G. Bandurraga, Lourdes M. Nogueira, Rita Kramer, David P. Turner, Victoria J. Findlay. MicroRNA-510 as a predictive marker for response to platinum-based chemotherapy in triple negative breast cancer. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr A47.