MicroRNA-143 is Associated With Pathological Complete Response and Regulates Multiple Signaling Proteins in Breast Cancer

Technol Cancer Res Treat. 2019 Jan 1:18:1533033819827309. doi: 10.1177/1533033819827309.

Abstract

Almost 55% to 80% of patients with breast cancer have an unfavorable pathological complete response to chemotherapy. MicroRNAs are small noncoding RNAs involved in cancer progression; however, their utility as predictors of pathological complete response to neoadjuvant chemotherapy is unclear. Here, we investigated if miR-143 could discriminate between pathological complete response and no-polymerase chain reaction of patients with locally advanced triple negative breast cancer that have received a fluorouracil-cisplatin/paclitaxel-based neoadjuvant treatment. Data showed that miR-143 exhibited a significant low expression ( P < .0006) in patients that achieved pathological complete response in comparison to nonresponder group. Receiver operating characteristic curve analysis suggested that miR-143 could be a good predictor of pathological complete response (area under curve = 0.849, P < .0006). Moreover, Kaplan-Meier analysis indicated that before neoadjuvant therapy low levels of miR-143 were associated to increased disease free survival. To gain insights into cellular functions of miR-143, we firstly showed that miR-143 was severely repressed in breast cancer cell lines and tumors in comparison to normal mammary cells and tissues. Ectopic restoration of miR-143 using RNA mimics inhibited both cell proliferation and migration and sensitized breast cancer cells to cisplatin therapy in vitro. To decipher the signaling networks regulated by miR-143, we used a high-throughput enzyme-linked immunosorbent assay-based phosphorylation antibody array. Phospho-proteomic profiling revealed that miR-143 coordinately reduced the protein levels and phosphorylation status of multiple oncoproteins involved in AKT, WNT/β-catenin, SAPK/JNK, FAK, and JAK/STAT signaling pathways. Moreover, low miR-143 and high GSK3-β, RAF1, paxillin, and p21CIP1 expression levels in a large cohort of patients with breast cancer were associated with worst outcome. In summary, miR-143 could be a potential predictor of response to neoadjuvant therapy and it may function as a divergent regulator of diverse signaling networks to suppress cell proliferation and migration in breast cancer.

Keywords: breast cancer; cell migration; cell proliferation; miR-143; neoadjuvant therapy; pathological complete response; signaling pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism*
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Cell Movement
  • Cell Proliferation
  • Drug Resistance, Neoplasm
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • MicroRNAs / genetics*
  • Neoadjuvant Therapy*
  • Signal Transduction
  • Tumor Cells, Cultured

Substances

  • Biomarkers, Tumor
  • MIRN143 microRNA, human
  • MicroRNAs