Deciphering the Role of miR-2115-3p in Molecular Apocrine Breast Cancer

Abstract

Background: Breast cancer (BC) is the most prevalent cancer in women with around 2.3 million new cases reported on a yearly basis worldwide. Despite all the effort put into research on BC, the incidence and mortality rates are on the rise. BC is a disease with intra and inter heterogeneity which makes it a major health issue. One of the methods for sub-typing BC is by looking at the expression of three different receptors -estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2). As such, triple negative breast cancer (TNBC) -one subtype of BC- is negative for the three receptors. TNBC itself is also heterogenous and it overlaps with distinct subtypes, namely molecular apocrine (MA) and luminal androgen receptor (LAR) BCs. These subtypes are, even today, still misdiagnosed and poorly treated. To better understand MABC, the discovery of underlying mechanisms that allow its development and tumorigenesis is required. Many studies have shed the light on the roles of microRNAs (miRNAs) in the progression of many types of cancers including BC. miRNAs are small noncoding RNA molecules that are endogenously expressed, and their dysregulation is reported to be implicated in the development and progression of BC. According to in silico analysis and preliminary data on a cohort of TNBC tumors, one of the miRNAs that is significantly upregulated in MABC is miR-2115-3p. miR-2115-3p is not widely reported in literature and very few studies have linked it to diseases other than BC which makes it novel. The aim of our study is to assess and investigate the role of miR-2115-3p in MABC’s progression using in vitro BC cellular models. The findings of this project will help in unraveling the functional role of miR-2115-3p in MABC tumorigenesis and might give insight to advance therapeutic approaches.

Methods and results: Dysregulation of miR-2115-3p in MABC was validated using in silico analysis based on miRNA data downloaded from The Cancer Genome Atlas (TCGA-BRCA) and a cohort of French BC samples. The impact of the miR-2115-3p on MABC tumorigenesis was investigated using non tumorigenic (MCF-10A) and BC cellular models of MABC (MDA-MB-453), and TNBC (MDA-MB-231). The models were established based on the expression of AR and the dysregulation of miR-2115-3p. miR-2115-3p showed a significant effect on proliferation and invasion in the cellular models. Finally, we looked for potential target genes for miR-2115-3p; however, we were not able to find a direct target for our miRNA.

Conclusion: Overall, our study suggests the potential of miR-2115-3p to be active players in MABC. We found that the modulation of miR-2115-3p significantly promotes proliferation and invasion in our MABC model. However, further studies are required to fully understand its function and validate the genes that it targets.