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

Available for download on Thursday, December 13, 2018

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