Date of Graduation
12-2017
Document Type
Dissertation (PhD)
Program Affiliation
Cancer Biology
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Khandan Keyomarsi, Ph.D.
Committee Member
Powel Brown, M.D., Ph.D.
Committee Member
Gary Gallick, Ph.D.
Committee Member
Stacy Moulder, M.D., M.S.
Committee Member
David McConkey, Ph.D.
Abstract
Almost seventy percent of patients with breast cancer have tumors that express hormone receptors and need hormonal therapy. Aromatase inhibitors (AIs) block estrogen biosynthesis and are considered as the first line hormonal therapy for ER+ post-menopausal patients. However, resistance to these drugs remains a major challenge in clinic and the biology of such resistance is not completely understood. Cyclin E is deregulated in breast cancer through generation of low molecular weight isoforms that renders patients to a poor survival. Herein, we show that HR+ patients with LMW-E expressing tumors show diminished early response to neo-adjuvant AIs as well as poor recurrence-free survival. In addition, xenografts with LMW-E expression are unresponsive to letrozole. Using LMW-E inducible model system, we show that LMW-E expression bypasses cell cycle inhibition of AIs through up-regulation of CDK2, Rb, and phospho-Rb in a reversible manner. Lastly, we show that LMW-E expressing breast cancer cells respond to dinaciclib but not palbociclib. Taken together, this study suggests that targeting CDK2 by inhibitors such as dinaciclib in combination with AIs is a potential therapeutic strategy for HR+ postmenopausal breast cancer patients with LMW-E expressing tumors.
Keywords
aromatase inhibitors, neoadjuvant, resistance, cytoplasmic cyclin E, breast cancer