MicroRNAs Discriminate Familial from Sporadic Non-BRCA1/2 Breast Carcinoma Arising in Patients ≤35 Years

Abstract

The influence of genetic factors may contribute to the poor prognosis of breast cancer (BC) at a very young age. However BRCA1/2 mutations could not explain the majority of cases arising in these patients. MicroRNAs (miRs) have been implicated in biological processes associated with BC. Therefore, we investigated differences in miRs expression between tumors from young patients (≤35 years) with sporadic or familial history and non-carriers of BRCA1/2 mutations. Thirty-six young Brazilian patients were divided into 2 groups: sporadic (NF-BC) or familial breast cancer (F-BC). Most of the samples were classified as luminal A and B and the frequency of subtypes did not differ between familial or sporadic cases. Using real time qPCR and discriminant function analysis, we identified 9 miRs whose expression levels rather than miR identity can discriminate between both patient groups. Candidate predicted targets were determined by combining results from miRWalk algorithms with mRNA expression profiles (n = 91 differently expressed genes). MiR/mRNA integrated analysis identified 91 candidate genes showing positive or negative correlation to at least 1 of the 9 miRs. Co-expression analysis of these genes with 9 miRs indicated that 49 differentially co-expressed miR-gene interactions changes in F-BC tumors as compared to those of NF-BC tumors. Out of 49, 17 (34.6%) of predicted miR-gene interactions showed an inverse correlation suggesting that miRs act as post-transcriptional regulators, whereas 14 (28.6%) miR-gene pairs tended to be co-expressed in the same direction indicating that the effects exerted by these miRs pointed to a complex level of target regulation. The remaining 18 pairs were not predicted by our criteria suggesting involvement of other regulators. MiR–mRNA co-expression analysis allowed us to identify changes in the miR-mRNA regulation that were able to distinguish tumors from familial and sporadic young BC patients non-carriers of BRCA mutations.

TGFbeta and miRNA regulation in familial and sporadic breast cancer

“…The role of miRNAs in both familial and sporadic BC has been previously investigated. In particular, Bastos EP and coworkers identified a miRNA signature capable to discriminate familial from sporadic non-BRCA1/2 breast carcinoma in patients younger than 35 years [ 11 ]. Moreover, other reports revealed the function of miRNAs in detecting BRCA genetic or epigenetic alterations in hereditary and sporadic breast tumors or finally, in discerning sporadic and BRCA1 associated basal-like BC [ 12 – 14 ].…”

“…The role of miRNAs in familial and sporadic breast tumors has been well explored [ 11 – 14 ] but few data are available about miRNAs involvement in HRR control in these BC subgroups. Taking into account the relevance of the identification of sporadic tumors with BRCA-like behavior useful to PARPi treatment [ 15 ], our aim was to seek miRNAs associated to pathways underlying DNA repair dysfunction in BC according to a family history of the disease.…”

MiRNA-210: A Current Overview

“…The overexpression of miR-210 in breast cancer is correlated with a poor prognosis, being associated with aggressiveness and shorter time to distant metastasis (80)(81)(82). miR-210 was shown to be upregulated in triple-negative breast cancer (TNBC), defined by the lack of estrogen receptor, progesterone receptor, and HER2 gene amplification, compared with estrogen positive breast cancer (83,84). miR-210 is overexpressed in numerous cancers including breast (85) and the induction of miR-210 is a consistent characteristic of the hypoxic response in both normal and transformed cells as we described in the section before but Bar et al interestingly suggested that miR-210 expression is regulated by a mechanism independent of HIF1alpha in infiltrated immune cells of the TNBC (86).…”

A Set of miRNAs, Their Gene and Protein Targets and Stromal Genes Distinguish Early from Late Onset ER Positive Breast Cancer

“…Various studies described the roles of miRs as either tumor suppressors or oncogenes in breast cancers, depending on which genes or pathways they affect in a specific cellular context [ 23 ]. However, few studies addressed the role of miRs expression and their targets in BC occurring in early onset patients [ 24 , 25 ].…”