MicroRNAs miR-7 and miR-340 predict response to neoadjuvant chemotherapy in breast cancer

Abstract

Purpose miRNAs have been linked to chemosensitivity of breast cancer cells in-vitro. In patients, however, there is no clinically validated method for predicting chemotherapy response. The aim of this study was to assess whether I) a specific pattern of miRNA expression in pretherapeutic biopsies can predict response to neoadjuvant chemotherapy, and II) differential miRNA expression in residual tumor after completion of chemotherapy allows further prognostic stratification of non-responding patients. Methods Sixty-four patients with newly diagnosed large (≥3cm) or locally advanced primary breast cancers who underwent neoadjuvant anthracycline/taxane-based chemotherapy were included. Relative expression of 10 miRNAs likely to be associated with chemotherapy response (miR-7,-21,-29a,-29b,-34a,-125b,-155,-200c,-340,-451) was determined by quantitative RT-PCR from pretherapeutic biopsies (n=64) and residual invasive tumor after chemotherapy (n=42). Pathologic complete response (pCR) defined by absence of invasive tumor served as reference standard. In addition, miRNA expression was compared with disease-free and overall-survival. Results Nine (14%) of 64 patients achieved pCR. High expression of miR-7 and low expression of miR-340 in pretherapeutic biopsies predicted pCR with a negative-predictive-value of 96% and 97%, respectively (specificity 54% and 57%). The combined profile of miR-7high/miR-340low demonstrated improved specificity of 86% while maintaining a high negative-predictive-value (96%) to identify non-responders. Pretherapeutic expression of miR-200c and miR-155 showed prognostic information and low expression was associated with increased overall survival (115 vs. 90 months, p≤0.03). After chemotherapy, the overall survival of patients with residual invasive tumor was better for those demonstrating low miR-7 or high miR-125b (p=0.01). Conclusions Intratumoral expression of miR-7 and miR-340 prior to neoadjuvant chemotherapy could be used to predict pCR and a profile of miR-7low or miR-340high identified patients unlikely to achieve pCR who might benefit from alternative treatment options including earlier surgery. Our study identifies miRNAs as promising predictive biomarkers, which could aid in optimization of breast cancer management and treatment stratification.

Differential expression of exosomal miRNAs between breast cancer patients with and without recurrence

“…Regarding miR-340-5p, the patients with recurrence had higher levels of miR-340 at their primary site as well as in the serum. Several studies have suggested the role of miR-340 as tumor suppressor gene [ 45 , 46 ], but one report demonstrated the association between miR-340 and chemoresistance [ 47 ]. Raychaudhuri et al reported that the patients with high expression of miR-340 in pretherapeutic biopsies in breast cancer were less likely to achieve pathological complete response (pCR).…”

“…Raychaudhuri et al reported that the patients with high expression of miR-340 in pretherapeutic biopsies in breast cancer were less likely to achieve pathological complete response (pCR). MiR-340 is predicted to regulate several genes which are associated with tumor growth and proliferation including Jun- and Fos oncogene, and Cyclin Dependent Kinase 5 [ 47 ].…”

Competing endogenous RNA (ceRNA) cross talk and language in ceRNA regulatory networks: A new look at hallmarks of breast cancer

“…The miR‐7‐5p upregulation reportedly inhibits cell proliferation and induces apoptosis of BC cells and tissues in vitro and in vivo (Y. Shi et al, ). Also, studies have shown that miR‐7‐5p directly targets Raf1 gene during lapatinib‐induced metastasis by IL‐6 expression in triple‐negative BC, and its reduced expression plays a key role in resistance of BC to neoadjuvant chemotherapy (Hsiao et al, ; Raychaudhuri et al, ). Notably, Raf1 gene has a crucial function in activating PI3K/Akt signaling pathway which has been shown to be complicated in the drug resistance of BC cells (Yuan Miao et al, ).…”

miR‑532‑5p promotes breast cancer proliferation and migration by targeting RERG

“…Differentially expressed miRNAs have been shown to be associated with different molecular subtypes of breast cancer (13). Several miRNAs, whose expression is associated with the clinical outcomes of breast cancer, serve as oncogenes or tumor suppressors in breast cancer (14)(15)(16). Recently, miR-532-5p was demonstrated to be significantly upregulated in TNBC tissues compared with normal breast tissues (17).…”