Prostate and breast cancers are the second leading causes of death in males and females respectively. Prostate tumors and most breast tumors depend, at least initially, upon circulating hormones for their growth and development. Estrogen antagonists and androgen antagonists comprise the most widely-used endocrine therapies for breast cancer and prostate cancer, respectively. While initial responses to hormone deprivation are the norm, most tumors eventually recur in what is termed a hormone-independent (antagonist-refractory) state. The molecular mechanisms of this resistance are not defined, and this lack of information impedes the rational design of improved anti-breast or -prostate cancer drugs. In the initial application, we proposed the novel concept that hormone antagonists, rather than simply blocking agonist-generated transcriptional and proliferative signals, actually initiate discrete antagonist-specific signaling pathway(s), which both: i.) block AR- or ER-responsive transcriptional responses;and ii.) also act upon the E2F node to block cell-cycle progression. In the course of the first two years of support under this grant, we have discovered a number of novel molecular mechanisms involved in estrogen antagonist- and androgen antagonist-induced transcriptional suppression and growth suppression of breast cancer cells and prostate cancer cells, including class III histone deacetylases, co-repressors, chromatin-modifying complexes, DNA-binding transcription factors, and protein kinases. These components are recruited to hormone-receptor complexes at responsive promoters by antagonists and comprise new signaling pathways activated by hormone antagonists. Loss of any of these signaling components renders the tumor cell refractory to hormone antagonists. In this renewal, in the first two Specific Aims, we will explore the mechanisms through which these factors act upon the antagonist-bound hormone-receptor complexes on responsive promoters to modulate transcription. The composition of the repressor complexes on native, endogenous hormone-responsive promoters will be studied through endogenous ChIP assays, and the interaction of these components with each other on responsive promoters will be analyzed through knock-down, and mutational, analyses. In the Third Specific Aim, the mechanisms through which these signaling pathways converge upon the E2F node to block cell cycle progression will be analyzed. Finally, the mechanistic consequences of natural loss or mutation of these antagonist-signaling components upon cellular responses to antagonists will be elucidated, and correlated with the functions of the components. Collectively, this work will define a new paradigm of nuclear hormone-receptor signaling, and will provide important information relevant to our current approaches to treating hormone-responsive and hormone- refractory tumors, which may be used both prognostically, and for the design of improved therapeutics.

Public Health Relevance

Hormone antagonists comprise the most widely-used endocrine therapies for breast and prostate cancer, but most tumors eventually recur in what is termed a hormone-refractory state. In the initial application, we proposed the novel concept that hormone antagonists actually initiate discrete antagonist-specific signaling pathway(s), which both alter transcriptional responses and also act upon the E2F node to block cell-cycle progression. In the course of the first two years of support under this grant, we have discovered a number of novel molecular mechanisms involved in hormone antagonist-induced transcriptional suppression and growth suppression of cancer cells, and loss of any of these signaling components renders the tumor cell refractory to hormone antagonists.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA101992-09
Application #
8408800
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Sathyamoorthy, Neeraja
Project Start
2003-06-01
Project End
2014-12-31
Budget Start
2013-01-01
Budget End
2014-12-31
Support Year
9
Fiscal Year
2013
Total Cost
$237,315
Indirect Cost
$91,275
Name
Boston University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Zhu, Lijia; Chiao, Christine Y; Enzer, Katelyn G et al. (2015) SIRT1 inactivation evokes antitumor activities in NSCLC through the tumor suppressor p27. Mol Cancer Res 13:41-9
Zhu, Lijia; Qi, Ji; Chiao, Christine Ya-Chi et al. (2014) Identification of a novel polyprenylated acylphloroglucinol?derived SIRT1 inhibitor with cancer?specific anti-proliferative and invasion-suppressing activities. Int J Oncol 45:2128-36
Moore, Robert L; Faller, Douglas V (2013) SIRT1 represses estrogen-signaling, ligand-independent ER?-mediated transcription, and cell proliferation in estrogen-responsive breast cells. J Endocrinol 216:273-85
Moore, R L; Dai, Y; Faller, D V (2012) Sirtuin 1 (SIRT1) and steroid hormone receptor activity in cancer. J Endocrinol 213:37-48
Boosalis, Michael S; Castaneda, Serguei A; Trudel, Marie et al. (2011) Novel therapeutic candidates, identified by molecular modeling, induce ýý-globin gene expression in vivo. Blood Cells Mol Dis 47:107-16
Byles, Vanessa; Chmilewski, Laura K; Wang, Joyce et al. (2010) Aberrant cytoplasm localization and protein stability of SIRT1 is regulated by PI3K/IGF-1R signaling in human cancer cells. Int J Biol Sci 6:599-612
Lambert, James R; Eddy, Vikram J; Young, Christian D et al. (2010) A vitamin D receptor-alkylating derivative of 1ýý,25-dihydroxyvitamin D3 inhibits growth of human kidney cancer cells and suppresses tumor growth. Cancer Prev Res (Phila) 3:1596-607
Perrine, Susan P; Mankidy, Rishikesh; Boosalis, Michael S et al. (2009) Erythroid Kruppel-like factor (EKLF) is recruited to the gamma-globin gene promoter as a co-activator and is required for gamma-globin gene induction by short-chain fatty acid derivatives. Eur J Haematol 82:466-76
Zhang, Baohua; Faller, Douglas V; Wang, Sheng (2009) HIC1 regulates tumor cell responses to endocrine therapies. Mol Endocrinol 23:2075-85
Zhang, B; Chambers, K J; Leprince, D et al. (2009) Requirement for chromatin-remodeling complex in novel tumor suppressor HIC1-mediated transcriptional repression and growth control. Oncogene 28:651-61

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