Electronic Thesis and Dissertation Repository

Degree

Master of Science

Program

Physiology and Pharmacology

Supervisor

Dr. Moshmi Bhattacharya

Abstract

Kisspeptins signal via the G-protein coupled receptor, KISS1R, and act as metastasis suppressors in numerous cancers. In estrogen receptor (ERα)-negative breast cancer cells, however, KISS1R signaling promotes cell invasion by activating the epidermal growth factor receptor (EGFR). Unfortunately, clinical success of anti-EGFR therapeutics has been limited, as patients often develop drug resistance. Recently, another receptor tyrosine kinase, AXL, has been shown to promote breast cancer drug resistance. We hypothesize that KISS1R promotes EGFR expression and induces breast cancer drug resistance. We demonstrated that KISS1R increases EGFR transcription, by increasing SP-1 binding to the EGFR promoter, as demonstrated by chromatin immunoprecipitation experiments. Additionally, we discovered that KISS1R signaling promotes drug resistance of ERα-negative breast cancer cells, since KISS1R overexpression decreased intracellular doxorubicin accumulation and decreased sensitivity. KISS1R also promotes AXL expression and AXL depletion restored doxorubicin sensitivity. Overall, our results suggest that KISS1R signaling promotes ERα-negative breast cancer drug resistance and may be a novel target to restore drug sensitivity.

Available for download on Sunday, June 16, 2019


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