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Mechanism of tamoxifen resistance in breast cancer

Author

Khyati Niral Shah, University of the Pacific

Date of Award

2014

Document Type

Dissertation - Pacific Access Restricted

Degree Name

Doctor of Philosophy (Ph.D.)

Department

Pharmaceutical and Chemical Sciences

First Advisor

Jesika Faridi

First Committee Member

Howard Elford

Second Committee Member

Jesika Faridi

Third Committee Member

John Livesey

Fourth Committee Member

Timothy Smith

Fifth Committee Member

Lisa Wrischnik

Abstract

Acquired tamoxifen resistance develops in the majority of hormone responsive breast cancers and frequently involves overexpression of the PI3K/AKT axis. Here, breast cancer cells, with elevated endogenous AKT or overexpression of activated AKT exhibited tamoxifen-stimulated cell proliferation and enhanced cell motility. To gain mechanistic insight on AKT-induced endocrine resistance, gene expression profiling was performed to determine the transcripts that are differentially expressed post-tamoxifen therapy under conditions of AKT overexpression. Consistent with the biological outcome, many of these transcripts function in cell proliferation and cell motility networks and were quantitatively validated in a larger panel of breast cancer cells. Moreover, ribonucleotide reductase M2 (RRM2) was revealed as a key contributor to AKT-induced tamoxifen resistance. Inhibition of RRM2 by RNAi-mediated approaches significantly reversed the tamoxifen-resistant cell growth, inhibited cell motility, and activated pro-apoptotic pathways. In addition, treatment of tamoxifen-resistant breast cancer cells with the small molecule RRM2 inhibitor Didox significantly reduced cell growth in vitro and in vivo. To further establish a functional association between RRM2 expression and tamoxifen resistance in breast cancer cells, gain of function studies were performed by overexpressing RRM2 in MCF-7 cells. Overexpression of RRM2 profoundly reduced tamoxifen sensitivity and down-regulated ER-&agr; in otherwise tamoxifen sensitive breast cancer cells. Furthermore, breast cancer cells with high RRM2 had elevated Her-2 and EGFR expression, modulated ER-&agr; signaling and NFκB expression. These findings also indicate that it may be possible to use RRM2 as a prognostic factor in breast cancer patients under tamoxifen therapy, and can be considered a potential therapeutic target in tumors that have acquired resistance to tamoxifen. Finally, inhibition of RRM2 by drug Didox effectively eradicates the tamoxifen resistant population, revealing a potential beneficial effect of combination therapy that includes RRM2 inhibition to delay or abrogate tamoxifen resistance. In conclusion, the findings of this work delineate the important role of RRM2 in Akt induced and acquired tamoxifen resistance in breast cancer. It also provides a preclinical rationale for evaluating tamoxifen in combination with Didox for breast cancer treatment.

Pages

163

ISBN

9781321285116

Recommended Citation

Shah, Khyati Niral. (2014). Mechanism of tamoxifen resistance in breast cancer. University of the Pacific, Dissertation - Pacific Access Restricted. https://scholarlycommons.pacific.edu/uop_etds/138

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 4.0 International License.