Master of Science
Dr. Eva Turley
Tumor heterogeneity and lack of targeted therapies are major hurdles in triple-negative breast cancer (TNBC) management. Elevated hyaluronan (HA) is a prognostic factor for poor outcome in TNBC. The TNBC MDA-MB-231 cell line contains highly metastatic but slow growing subpopulations that bind high levels of HA. I show these subpopulations express elevated HAS2, RHAMM and PGA3, and are more resistant to doxorubicin but more sensitive to MEK1 targeted therapy than parental cells or low HA binding subpopulations. Databank mining show HAS2, RHAMM, and PGA3 are significantly associated with chemotherapy-treated BCa. Knockout of RHAMM using CRISPR/Cas9 gene editing reduced localization of active ERK1/2 to nuclei and sensitivity to MEK1 targeted therapy. These results show that RHAMM and likely HA are factors in TNBC subset in susceptibility to MEK inhibition, and that it is a potential biomarker for TNBC patients with sensitivity to MEK1 therapy.
Vakili, Tahereh, "An invasive tumor cell subpopulation as a therapeutic target in breast cancer" (2017). Electronic Thesis and Dissertation Repository. 5104.