Clinical and biological impact of miR-18a expression in breast cancer after neoadjuvant chemotherapy

• Published in: Cellular oncology (Dordrecht) Vol. 42; no. 5; pp. 627 - 644
• Main Authors: Luengo-Gil, Ginés, García-Martínez, Elena, Chaves-Benito, Asunción, Conesa-Zamora, Pablo, Navarro-Manzano, Esther, González-Billalabeitia, Enrique, García-Garre, Elisa, Martínez-Carrasco, Alberto, Vicente, Vicente, Ayala de la Peña, Francisco
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer Netherlands 01-10-2019; Springer Nature B.V
• Subjects: Adult; Aged; Biomarkers; Biomarkers, Tumor - metabolism; Biomedical and Life Sciences; Biomedicine; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - mortality; Breast Neoplasms - pathology; Cancer Research; Cancer therapies; Cell Cycle Proteins - metabolism; Cell proliferation; Chemotherapy; Chemotherapy, Adjuvant - mortality; Disease-Free Survival; Estrogen receptors; Female; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Humans; Ki-67 Antigen - metabolism; MCF-7 Cells; Menopause; MicroRNAs - antagonists & inhibitors; MicroRNAs - genetics; MicroRNAs - metabolism; Middle Aged; miRNA; Neoadjuvant Therapy; Oncology; Original Paper; Pathology; Patients; Prognosis; Receptors, Estrogen - antagonists & inhibitors; Receptors, Estrogen - metabolism; Retrospective Studies; Tamoxifen; Tamoxifen - pharmacology; Trans-Activators - metabolism; Transcriptome; Tumor cell lines; Tumors; Neoadjuvant chemotherapy; Prognostic markers; miR-17-92a; Endocrine resistance; Breast cancer; miR-18a
• ISSN: 2211-3428; 2211-3436
• DOI: 10.1007/s13402-019-00450-2

Purpose
The analysis of breast cancer residual tumors after neoadjuvant chemotherapy (nCT) may be useful for identifying new biomarkers. MicroRNAs are known to be involved in oncogenic pathways and treatment resistance of breast cancer. Our aim was to determine the role of miR-18a, a member of the miR-17-92a cluster, in breast cancer behavior and outcome after nCT.
Methods
Pre- and post-nCT tumor miR-18a expression was retrospectively assessed by qRT-PCR in 121 patients treated with nCT and was correlated with survival outcomes and with clinical and pathological characteristics. Breast cancer-derived MCF-7 and MDA-MB-231 cell lines were transfected with miR-18a and anti-miR-18a to evaluate the biological effects of this molecule. In addition, whole-transcriptome expression analysis was performed.
Results
High miR-18a expression in post-nCT residual tumors was found to be associated with a significantly worse overall survival [hazard ratio (HR): 2.80, 95% confidence interval (CI): 1.01–7.76] and a strong trend towards a poorer disease-free survival (HR: 2.44, 95% CI: 0.99–5.02) compared to low miR-18a expressing post-nCT residual tumors. Clinical and experimental data were found to be in conformity with the proliferative effects of miR-18a, which showed a significant correlation with Ki67 and MYBL2 expression, both in pre- and post-nCT tumors and in public databases. In vitro analysis of the role of miR-18a in breast cancer-derived cell lines showed that a high expression of miR-18a was associated with a low expression of the estrogen receptor (ER), a decreased sensitivity to tamoxifen and an enrichment in luminal B and endocrine resistance gene expression signatures.
Conclusions
From our data we conclude that post-nCT miR-18a expression in breast cancer serves as a negative prognostic marker, especially in luminal tumors. Clinical, in vitro and in silico data support the role of miR-18a in breast cancer cell proliferation and endocrine resistance and suggest its potential utility as a biomarker for additional adjuvant treatment in patients without a pathologic complete response to neoadjuvant therapy.