MicroRNA-181a/b: Novel biomarkers to stratify breast cancer patients for PARPi treatment

Deregulation of the DNA damage response (DDR) is a main feature of cancer progression and a common finding in breast cancer. While a clear correlation between mutations of BRCA1/2 and ATM in cancer development has been found in hereditary breast cancers, the molecular basis of DDR deregulation of sporadic breast cancers is still unclear. Triple-negative (TNBC) and basal-like (BLBC) breast cancers are very aggressive sporadic tumors that relapse very frequently. Only 2% of sporadic tumors bear detectable BRCA1/2 and ATM mutations. Interestingly, TNBCs and BLBCs present a histoclinical phenotype comparable to that observed in patients with hereditary germline BRCA1/2 mutations (“BRCAness” phenotype). However, while BRCA1 mutated breast cancers are sensitive to PARP inhibitors, both TNBCs and BLBCs are poorly responsive to anticancer treatments. Recent evidence has shown that the altered expression of microRNA genes can be associated with diverse types of cancers. microRNAs are small non-coding RNA molecules that negatively regulate gene expression at the post-transcriptional level. They bind through partial sequence homology to the 3′-untranslated region of target mRNAs and cause translational inhibition and/or mRNA degradation. In the June 1, 2013 issue of Cell Cycle, Del Sal’s group surveyed public breast cancer data sets for miR-181a/b expression.¹ They found that increased expression of miR-181a/b correlated with shorter disease-free survival and early onset of metastatic disease. The expression of miR-181a/b was also assessed on more than 100 primary breast cancer samples and was found upregulated in tumor specimens when compared with normal tissues. This also correlated with tumor aggressiveness. miR-181a/b have been shown to promote migration and invasion of breast cancer cells as well as the expansion of breast cancer stem-like cells.² miR181a/b expression is regulated by transforming growth factor-b,^3-5 whose pathway is aberrantly activated in breast cancer transformation.^6,7 At the molecular level, Del Sal group showed that miR-181a/b targeted ATM mRNA, thereby impinging severely on DDR response of breast cancer cells. BRAC1 phosphorylation was reduced in miR181a/b-overexpressing cells, suggesting that miR-181a/b increased expression may dampen DDR and DNA double-strand breaks repair, leading to the accumulation of unfixed DNA lesions in breast cancer cells. This might unveil the oncogenic value of miR-181a/b overexpression and lead to the development of potential therapeutic strategies aimed at overcoming its pro-tumorigenic effects in breast cancers. It is becoming increasingly clear that a detailed molecular cancer portrait of a single patient is required to design the most effective cancer treatment. This is ineludible, as the development of resistance to target therapy for diverse types of tumors, including breast cancer, significantly increases. Indeed, chemoresistance remains a major clinical obstacle to successful treatment of breast cancer and a source of poor prognosis. The power of cancer patient response prediction to given treatments needs to be strongly improved. It is reasonable to think that the more molecular variables we can include in the prediction model the better prediction we may expect. Notably, in this issue of Cell Cycle, Bisso and colleagues reported that miR-181a/b overexpressing cells are sensitive to pharmacological inhibition of PARP. miR-181a/b overexpression sensitized breast cancer cells to PARP inhibition, as for Olaparib (AstraZeneca). This raises the intriguing possibility that overexpression of miR-181a/b could be regarded as a potential biomarker that allows the identification of a subgroup of TNBC and BLBC patients who may benefit from the treatment with PARPi. The miR-181a/b overexpression Del Sal’s group observed in diverse tumors types could also have major implications for other types of human cancers. In light of these findings, additional work attempting the functional validation of novel miR-181a/b mRNA targets might provide novel insight into the molecular characterization of aggressive cancer subtypes and hold important therapeutic potential. (Fig 1)

Figure 1. Hereditary breast cancers and sporadic breast cancers presenting BRCA1 mutations account for the 12% of the total breast tumors. Basal-like and triple-negative breast cancers among the sporadic breast tumors (88%) that present “BRCAness” phenotype and may be screened for miR-181a/b expression to treat selectively with PARP inhibitor.

Bisso A, Faleschini M, Zampa F, Capaci V, De Santa J, Santarpia L, et al. Oncogenic miR-181a/b affect the DNA damage response in aggressive breast cancer. Cell Cycle. 2013;12