ORIGINAL PAPER Downregulation of miR-34a in breast tumors is not associated with either p53 mutations or promoter hypermethylation while it correlates with metastasis Arash Javeri • Massoud Ghaffarpour • Masoumeh Fakhr Taha • Massoud Houshmand Received: 11 November 2012 / Accepted: 14 November 2012 Ó Springer Science+Business Media New York 2013 Abstract MicroRNA-34 family has anti-proliferative and apoptotic roles. Recent studies have shown that p53 upregulates miR-34 family leading to direct repression of several key oncogenes. Inactivation of miR-34a has been reported in mul- tiple types of malignancies including breast cancer. The critical role of miR-34a in p53-mediated cell cycle arrest and apoptosis invokes studies focusing on the specific role of miR-34a dys- regulation in carcinogenesis. While presence of p53 mutations has frequently been described in breast cancer, still most of the breast tumors do not show any variation in the p53 coding sequence or protein expression. Therefore, it is important to clarify possible involvement of other mediators of p53 pathway in breast cancer. In this study, expression of mature miR-34a in breast tumors with wild-type p53 was investigated in order to find any correlation between dysregulation of miR-34a expression and breast cancer. In about 40 % of the wild-type p53 samples, miR-34a was significantly downregulated. Nei- ther hypermethylation of the miR-34a promoter nor genetic variations of the p53-binding site were detected in tumor samples with downregulated miR-34a. This study has provided evidence that miR-34a expression can be affected in a signifi- cant proportion of breast tumors independent of p53. Further- more, downregulation of miR-34a was significantly associated with metastasis, while there was a significant correlation between upregulation of miR-34a and non-metastatic condition indicating a protective role for miR-34a against more invasive disease. Knowledge of miR-34a status may provide additional useful information regarding the nature of breast tumors, especially when p53 testing does not show any aberration. Keywords Breast cancer Á miR-34 Á p53 Á Metastasis Introduction Cancer is a multi-stage process during which normal cell acquires a complex of several alterations in cell physiology including self-sufficiency, resistance to growth-inhibitory signals and apoptosis, unlimited replicative capacity, con- tinuous angiogenesis and metastasis [1]. MicroRNAs include a class of non-coding small RNAs, consisting of about 22 nucleotides in length [2]. They are principally involved in post-transcriptional regulation of gene expres- sion and affect all main aspects of cellular physiology including developmental transitions, stress response, metabolism, proliferation and apoptosis [3]. These mecha- nisms are frequently altered during malignant transforma- tion. Epigenetic changes including dysregulation of miRNAs have been increasingly described as an important player in cancer development during recent years [4–8]. Members of miR-34 family, including miR-34a, b and c, were reported as direct targets of p53 protein by several investigators in 2007 [9–15]. These studies showed that upregulation of miR-34 family by p53 leads to cell cycle arrest and apoptosis through its inhibitory effect on some key regulators of cell cycle progression, like E2F3, BCL-2, c-Myc, CDK4, etc. [15]. However, miR-34a has been iden- tified as the major form of miR-34 family induced after p53 activation [10, 12–15]. P53 gene mutations have been reported in almost all types of cancer, and existence of these mutations has usually been regarded as a poor prognostic A. Javeri (&) Á M. Ghaffarpour Á M. F. Taha Á M. Houshmand Department of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), P.O. Box: 161-14965, Tehran, Iran e-mail: arashj@nigeb.ac.ir M. Ghaffarpour Iranian Research Organization for Science and Technology (IROST), Tehran, Iran 123 Med Oncol (2013) 30:413 DOI 10.1007/s12032-012-0413-7