Triple Negative Breast Cancer (TNBC) accounts for 15-20% of all BC cases. Prognosis for this subtype of Breast Cancer (BC) is especially dire due to the absence of ER, PR and HER-2 receptors usually targeted by targeted therapies. The identification of novel targeted therapies for TNBC is an urgent need. Another factor contributing to poor prognosis in TNBC is the development of chemoresistance. Chemoresistance is a leading cause of therapy failure and mortality in TNBC. Understanding the molecular mechanisms underlying chemoresistance in TNBC and other BCs is vital to developing effective ways to combat these malignancies. Drug efflux pump ABCB1 is a key contributor to chemoresistance in TNBC, where it removes a variety of chemotherapeutic agents from tumor cells. Because ABCB1 is ubiquitously expressed in cancerous and normal cells alike, attempts at overcoming chemoresistance by inhibiting ABCB1 directly have failed. Identifying cancer-specific upstream regulators of ABCB1 that can be targeted to repress chemoresistance is imperative. The work outlined here identifies a novel therapeutic agent for TNBC which targets TNBC cells with minimal effects on non-malignant cells. It also describes a novel upstream regulator of ABCB1 that can be targeted to repress chemoresistance. In aims I and II, we describe the selective anti-TNBC activity of Strictinin, a naturally occurring polyphenol isolated from Myrothamnus flabellifolius, a South African medicinal herb with anti-cancer properties. Strictinin targets ROR1, an oncofetal receptor highly expressed in several cancers but not expressed in normal adult cells making it an ideal target for cancer therapy. In aim III, we identified ROR1 as a key upstream regulator of ABCB1 and chemoresistance in TNBC that can be targeted to repress chemoresistance. We also describe the mechanism of ROR1 regulation of ABCB1. Altogether, the findings outlined here describe a novel selective anti-TNBC agent and propose ROR1-inhibition as a therapeutic strategy to combat chemoresistance in TNBC and other cancers.
|Advisor:||Peethambaran, Bela, Klase, Zachary A.|
|Commitee:||Pape-Zambito, Dana, Mercier, Isabelle|
|School:||University of the Sciences in Philadelphia|
|Department:||Cell & Molecular Biology|
|School Location:||United States -- Pennsylvania|
|Source:||DAI-B 81/10(E), Dissertation Abstracts International|
|Subjects:||Cellular biology, Molecular biology, Oncology, Pharmacology|
|Keywords:||Cancer therapy, Chemoresistance, Natural products, Strictinin, Triple negative breast cancer|
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