miR-10b as a mediator between obesity and primary breast cancer

Obesity is a risk factor for breast cancer (BC) in post-menopausal women, suggesting that shared molecular mechanisms contribute to the etiology and pathology of both obesity and cancer. Mounting evidence suggests that some of these mechanisms are regulated by microRNAs. Our study aims to better understand the roles of microRNAs as metabolic regulators of BC development.

We isolated total RNA from paired biopsies (healthy and tumor tissue) from 80 BC patients and the microRNA profile was characterized using RNA-seq in the 6 most overweight and 6 leanest patients in the group. The levels of candidate microRNAs were validated by qRT-PCR in the entire 80-patient cohort. Among microRNAs showing differential expression between normal and tumor samples was miR-10b, known to be upregulated in metastatic BC cells. However, in primary tumor cells the levels of miR-10b are known to decrease with the clinical progression of the disease, and this was supported by our findings. We found that obesity exacerbated the decrease in miR-10b in tumor compared to normal tissue, supporting the notion that the metabolic state of the organism can alter the molecular makeup of a tumor.

To characterize the molecular mechanisms that may be affected by this change in miR-10b levels, the expression of previously validated miR-10b targets was measured by qRT-PCR in the same cohort, and correlations were sought between mir-10b levels, target mRNA levels and clinical data. Expression of several targets, such as MAPRE1, showed inverse correlations with miR-10b levels, supporting the physiological/pathological relevance of regulation by miR-10b.

Future goals are to directly assess the roles of miR-10b by manipulating the levels of miR-10b in a primary tumor cell line (BT549) with miR-10b mimics and antagomiRs and conducting cancer-relevant cell assays such as proliferation and invasion. The upstream regulation of miR-10b will also be studied, by treating the cells with metabolic and inflammatory factors and measuring the effects on the levels of miR-10b, its target mRNAs, and cell behavior.

We hope that our study will help elucidate the role of miR-10b as a potential mediator between obesity and BC in postmenopausal women, which may have diagnostic and therapeutic potential.