Author ORCID Identifier

0000-0002-5413-849X

Date of Graduation

8-2018

Document Type

Dissertation (PhD)

Program Affiliation

Experimental Therapeutics

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Bulent Ozpolat M.D. Ph.D

Committee Member

Gabriel Lopez-Berestein M.D.

Committee Member

George A. Calin M.D. Ph.D

Committee Member

Zahid H. Siddik Ph.D

Committee Member

Prahlad Ram Ph.D

Abstract

Triple negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer (BC), with a poor prognosis with currently used therapies, and thus represents an unmet therapeutic challenge. Lack of molecular targets (i.e. ER, PR, HER2) and significant genetic heterogeneity are the major reasons contributing to early relapse and high mortality rates. Numerous studies have indicated that microRNAs (miRs) have an important role in BC progression, invasion, angiogenesis, and metastasis. We analyzed miRNA expression profiles of BC patient data bases and identified that miR-484 is highly upregulated in all subtypes of BC patients, with the highest expression in TNBC patients. miR-484 was found to be associated with significantly shorter patient survival, while inhibition of miR-484 in TNBC cells led to significant reduction of cell proliferation, motility and invasion, and induced cell cycle arrest and apoptosis. Furthermore, we found that miR-484 is inversely correlated with levels of HOXA5 in patients’ tumors and demonstrated that miR-484 directly binds to the 3¢-untranslated region (3¢-UTR) of HOXA5 mRNA to suppress its expression. Moreover, HOXA5 over-expression recapitulated the effects of miR-484 inhibition. In vivo therapeutic targeting of miR-484 by systemic administration of anti-miR-484 nanoparticles significantly induced HOXA5 expression and suppressed tumor growth and progression in orthotopic xenograft mouse models of TNBC. Thus, our findings provide new insights about the oncogenic role of miR-484 and suggest that miR-484 represents a novel therapeutic target in TNBC.

Keywords

miRNA, miR-484, Triple Negative Breast Cancer, HOXA5

Available for download on Thursday, August 15, 2019

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