Abstract 504: miR-484 acts as an “oncomiR” in triple negative breast cancer cells to promote tumor growth and progression by targeting HOXA5
Authors: Kabil Nashwa N. , Bayraktar Recep , Ivan Cristina , Kahraman Nermin , Mokhlis Hamada A. , Calin George A. , Lopez-Berestein Gabriel , Ozpolat Bulent 
Published: August 2018

Breast cancer (BC) is the most common malignancy and the second leading cause of cancer-related deaths in women worldwide. Triple negative breast cancer (TNBC) is the most aggressive and chemo-resistant subtype of BC that represents an unmet therapeutic challenge. Lack of therapeutic targets and significant tumor heterogeneity are the major reasons contributing to poor prognosis and high mortality rates. To meet these challenges, we extensively analyzed BC patient databases and discovered that the high expression of a novel non coding RNA- microRNA 484- was correlated with poor survival and prognosis of BC patients. Moreover, miR-484 expression was elevated in all molecular subtypes of BC patients, especially in TNBC, compared to healthy controls. Thus, our preliminary data suggests that miR-484 could be a possible oncogenic driver, with clinical and prognostic significance in BC patients, and may thus serve as a potential molecular target. However, the role and mechanism of action of miR-484 in TNBC has not been previously elucidated. Thus, the aim of this study is to elucidate the functional role and mechanism of action of miR-484 in TNBC. To identify potential targets for miR-484, we used four different algorithms that predict the mRNA targets of miRNAs: TargetScan, miRDB, microrna.org, and Dianna microT, and based on their target prediction strategy, HOXA5 was the common target for miR-484 in all four databases. The homeobox protein (HOXA5) is a transcription factor that has been shown to play important roles in cell differentiation, hematopoiesis, and tumorigenesis. Additionally, previous studies have shown that HOXA5 may function as tumor suppressor in BC. Our results showed that ectopic inhibition of miR-484 reduced cell proliferation, colony formation, invasion/migration, and induced apoptosis in TNBC cells. Furthermore, ectopic overexpression of miR-484 reduced HOXA5 mRNA and protein expression levels in TNBC cells, suggesting that miR-484 may function in TNBC cells by inhibition of HOXA5. We further confirmed that HOXA5 is a direct target of miR-484 by luciferase reporter assay, and showed reduced luciferase activity in TNBC and HEK293 cells expressing the 3'UTR region of HOXA5 and treated with miR-484 mimic. Furthermore, in vivo therapeutic targeting of miR-484 significantly reduced tumor growth and progression in orthotopic xenograft TNBC mouse models. Overall, our findings suggest that miR-484 promotes tumor growth and progression by targeting HOXA5 in TNBC.

Citation Format: Nashwa N. Kabil, Recep Bayraktar, Cristina Ivan, Nermin Kahraman, Hamada A. Mokhlis, George A. Calin, Gabriel Lopez-Berestein, Bulent Ozpolat. miR-484 acts as an “oncomiR” in triple negative breast cancer cells to promote tumor growth and progression by targeting HOXA5 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 504.