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 effective in the clinic. We have developed a unique preclinical model in order to study the effects of aromatase inhibitors and antiestrogens in breast cancer. In this model, tumors of human estrogen receptor positive cells transfected with the aromatase gene (MCF-7Ca) are grown in athymic mice. The model has provided accurate predictions of clinical outcome. The proposed studies will continue the direction of the current grant focusing our efforts on several significant observations made during this period. Much remains to be learned about the mechanism of effects of aromatase inhibitors when used in different strategies of treatment. In this application, we propose studies to investigate mechanisms of resistance to aromatase inhibitors and how they might be reversed. Our preliminary data suggest that HER2 is increased in letrozole treated tumors and appears to be overexpressed in letrozole resistant tumor cells. The HER2 receptor is the protein product of the HER2 proto-oncogene. Phosphorylated HER2 can activate down stream signaling pathways involved in proliferation and tumor cell survival.
In Specific Aim 1, we plan to determine the expression of HER2 and MAPKinase in tumors harvested from mice following long-term treatment with letrozole and after second line treatment with antiestrogens. Studies are proposed to investigate the mechanism of letrozole resistance and the role of HER2 and MAPKinase in the tumor model (Specific Aim 2). In light of clinical findings that breast cancer patients with ER+ HER2+ tumors responded significantly better to letrozole than to tamoxifen, we will test the hypothesis, in Specific Aim 3, that tamoxifen but not letrozole leads to dimerization of the ER which can be phosphorylated by MAP kinase, the downstream mediator of HER2, and resulting in transcription. In the fourth Specific Aim, we will determine whether HER2 and MAPKinase inhibitors are effective in preventing the development of or overcoming resistance to letrozole in the xenograft model. ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA062483-23
Application #
6871956
Study Section
Biochemical Endocrinology Study Section (BCE)
Program Officer
Sathyamoorthy, Neeraja
Project Start
1980-09-01
Project End
2008-03-31
Budget Start
2005-04-12
Budget End
2006-03-31
Support Year
23
Fiscal Year
2005
Total Cost
$314,078
Indirect Cost
Name
University of Maryland Baltimore
Department
Pharmacology
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
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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