The long-term goal of this project is to develop strategies to improve the treatment of breast cancer. The aromatase inhibitors we pioneered in the early phases of this grant are now proving to be of value in the clinic. Although AIs appear to be more effective than tamoxifen, some patients may acquire resistance or have de novo resistance to AIs. The unique preclinical model we have developed to study the effect of aromatase inhibitors (AIs) has provided accurate predictions of clinical outcome. We propose to use this model to study mechanisms of tumor resistance. We have also developed unique tumors and cell lines that are resistant to letrozole and other AIs for use in these investigations. In the proposed studies, we will focus our efforts on several significant observations made during the current period. We plan to determine the mechanisms of resistance to aromatase inhibitors and how these might be reversed so that response to well tolerated AI treatment can be restored.
The Specific Aims of the proposal are: 1) to investigate the functional the role of HER2/MAPK in estrogen receptor regulation and development of resistance to AIs. We will explore whether other inhibitors of HER2, such as lapatinib, pertuzumab and HKI-272 also reverse resistance to letrozole;2) to investigate whether down-regulation of the estrogen receptor (ER) by fulvestrant prevents crosstalk with tyrosine kinase receptors (TKR) in AI resistance. We will determine whether combining an AI and estrogen down regulator is more effective than complete estrogen suppression in controlling tumor growth. Based on mechanisms identified, the optimal efficacy of these agents in combination or sequential strategies will be determined;3) to investigate mechanisms involved in reversing resistance of tumors to letrozole and other AIs following withdrawal of AI treatment;4) to investigate whether histone deacetylase (HDAC) inhibitors will convert ER negative cells to hormone responsive cells that are sensitive to HDACI + AI treatment and reduce the cancer progenitor cells or """"""""side population"""""""" in these and AI resistant cells and tumors. Our studies should provide information with which to plan new strategies to treat breast cancer patients.

Public Health Relevance

This competitive renewal application is to continue studies to understand the mechanisms involved in resistance of breast cancers to aromatase inhibitor treatment. Having identified mechanisms of resistance to aromatase inhibitors, we will then apply this information to develop strategies to reverse resistance and restore sensitivity to aromatase inhibitor treatment. These strategies will be tested in our unique model to determine their anti-tumor efficacy. The results of these studies could improve treatment for breast cancer patients.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
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Sathyamoorthy, Neeraja
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University of Maryland Baltimore
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Schech, Amanda J; Shah, Preeti; Yu, Stephen et al. (2015) Histone deacetylase inhibitor entinostat in combination with a retinoid downregulates HER2 and reduces the tumor initiating cell population in aromatase inhibitor-resistant breast cancer. Breast Cancer Res Treat 152:499-508
Khatri, Raju; Shah, Preeti; Guha, Rupa et al. (2015) Aromatase Inhibitor-Mediated Downregulation of INrf2 (Keap1) Leads to Increased Nrf2 and Resistance in Breast Cancer. Mol Cancer Ther 14:1728-37
Schech, Amanda J; Kazi, Armina A; Gilani, Rabia A et al. (2013) Zoledronic acid reverses the epithelial-mesenchymal transition and inhibits self-renewal of breast cancer cells through inactivation of NF-?B. Mol Cancer Ther 12:1356-66
Sabnis, Gauri J; Goloubeva, Olga G; Kazi, Armina A et al. (2013) HDAC inhibitor entinostat restores responsiveness of letrozole-resistant MCF-7Ca xenografts to aromatase inhibitors through modulation of Her-2. Mol Cancer Ther 12:2804-16
Sabnis, Gauri J; Kazi, Armina; Golubeva, Olga et al. (2013) Effect of selumetinib on the growth of anastrozole-resistant tumors. Breast Cancer Res Treat 138:699-708
Gilani, Rabia A; Kazi, Armina A; Shah, Preeti et al. (2012) The importance of HER2 signaling in the tumor-initiating cell population in aromatase inhibitor-resistant breast cancer. Breast Cancer Res Treat 135:681-92
Hursting, Stephen D; Digiovanni, John; Dannenberg, Andrew J et al. (2012) Obesity, energy balance, and cancer: new opportunities for prevention. Cancer Prev Res (Phila) 5:1260-72
Tobin, Lisa A; Robert, Carine; Nagaria, Pratik et al. (2012) Targeting abnormal DNA repair in therapy-resistant breast cancers. Mol Cancer Res 10:96-107
Schech, Amanda J; Nemieboka, Brandon E; Brodie, Angela H (2012) Zoledronic acid inhibits aromatase activity and phosphorylation: potential mechanism for additive zoledronic acid and letrozole drug interaction. J Steroid Biochem Mol Biol 132:195-202
Tilghman, Syreeta L; Sabnis, Gauri; Brodie, Angela M H (2011) Upregulation of AIB1, aromatase and ER* provides long-term estrogen-deprived human breast cancer cells with a mechanistic growth advantage for survival. Horm Mol Biol Clin Investig 3:357-366

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