Our long-term goal is to understand which roles BRCA1 plays in cellular activities and how its impairment leads to breast tumorigenesis. Although no BRCA1 mutation is found in the majority of sporadic breast cancers, its expression is down-regulated in 20-61% of the cases, extending the relevance of BRCA1 deficiency to the general breast cancer pathogenesis. We have previously elucidated the role of BRCA1 in DNA damage response and guarding genome stability through interacting with repair machinery proteins. However, BRCA1 as a full tumor suppressor must act to modulate cellular proliferation and differentiation. How BRCA1 executes such activities has not been fully developed. Previously, we identified a novel BRCA1-interacting protein, ZBRK1, which binds to a specific DNA sequence found in a subset of BRCA1 target genes, thus establishing a means by which BRCA1 is physically and functionally tethered to particular regulatory loci and serves as a co-repressor. We have also demonstrated that depletion of BRCA1, CtIP or ZBRK1 by RNAi in mammary epithelial cells (MECs) 3-D culture, a close mimicry of an in vivo environment, leads to MEC proliferation and impairs mammary acinus differentiation by altering the expression of genes including ANG1 (Angiopoietin1), HMGA2 (High Mobility Group AT-hook 2) and others. These results strongly support that BRCA1 has a critical role in governing MEC proliferation and differentiation. Importantly, factors secreted from normal differentiating MEC are able to inhibit breast cancer cell growth. Among these, we have identified IL17E (IL25) that kills breast cancer cells through caspase-mediated cell death pathway and inhibits tumorigenicity with non-detectable toxicity in animals, and BMP10 that also specifically inhibits breast cancer cell growth but not normal MEC. Based on these advances, we propose three specific aims to test the hypothesize that BRCA1 and its interacting partners coordinately regulate functionally diverse genes involved in proliferation and differentiation of MECs and modulating the microenvironment as follows:
Aim 1. To study the mode and consequence of transcriptional repression of ANG1 and HMGA2 mediated by BRCA1/ZBRK1;
Aim 2. To elucidate regulatory modes of BRCA1-mediated, but ZBRK1 independent, transcriptional modulation of FGF2, RFC1, TIP30 and TFDP1;
and Aim 3. To characterize factors of IL-17E and BMP10 secreted from differentiating MEC that kill breast cancer cells. We expect that the results obtained from this proposal will contribute significant to the future diagnosis and treatment of breast cancer because these BRCA1-modulated genes are oncogenic or tumor-suppressive in nature and have potential diagnostic and prognostic values. Especially, these natural factors that specifically suppress proliferation and induce breast cancer cell death will potentially provide a novel tumor dormancy therapy for treating breast cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA094170-11
Application #
8204548
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Mietz, Judy
Project Start
2002-01-18
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2013-12-31
Support Year
11
Fiscal Year
2012
Total Cost
$261,352
Indirect Cost
$87,691
Name
University of California Irvine
Department
Biochemistry
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Huang, C-K; Yang, C-Y; Jeng, Y-M et al. (2014) Autocrine/paracrine mechanism of interleukin-17B receptor promotes breast tumorigenesis through NF-*B-mediated antiapoptotic pathway. Oncogene 33:2968-77
Guo, Xuning Emily; Ngo, Bryan; Modrek, Aram Sandaldjian et al. (2014) Targeting tumor suppressor networks for cancer therapeutics. Curr Drug Targets 15:2-16
Furuta, Saori; Jeng, Yung-Ming; Zhou, Longen et al. (2011) IL-25 causes apoptosis of IL-25R-expressing breast cancer cells without toxicity to nonmalignant cells. Sci Transl Med 3:78ra31
Tyan, Shiaw-Wei; Kuo, Wen-Hung; Huang, Chun-Kai et al. (2011) Breast cancer cells induce cancer-associated fibroblasts to secrete hepatocyte growth factor to enhance breast tumorigenesis. PLoS One 6:e15313
Hwang-Verslues, W W; Chang, P-H; Wei, P-C et al. (2011) miR-495 is upregulated by E12/E47 in breast cancer stem cells, and promotes oncogenesis and hypoxia resistance via downregulation of E-cadherin and REDD1. Oncogene 30:2463-74
Ahmed, Kazi Mokim; Tsai, Connie Y; Lee, Wen-Hwa (2010) Derepression of HMGA2 via removal of ZBRK1/BRCA1/CtIP complex enhances mammary tumorigenesis. J Biol Chem 285:4464-71
Liao, Ching-Chun; Tsai, Connie Y; Chang, Wen-Chang et al. (2010) RBýýE2F1 complex mediates DNA damage responses through transcriptional regulation of ZBRK1. J Biol Chem 285:33134-43
Liu, Feng; Lee, Wen-Hwa (2006) CtIP activates its own and cyclin D1 promoters via the E2F/RB pathway during G1/S progression. Mol Cell Biol 26:3124-34
Furuta, Saori; Wang, Ju-Ming; Wei, Shuanzeng et al. (2006) Removal of BRCA1/CtIP/ZBRK1 repressor complex on ANG1 promoter leads to accelerated mammary tumor growth contributed by prominent vasculature. Cancer Cell 10:13-24
Chen, Phang-Lang; Liu, Feng; Cai, Suna et al. (2005) Inactivation of CtIP leads to early embryonic lethality mediated by G1 restraint and to tumorigenesis by haploid insufficiency. Mol Cell Biol 25:3535-42

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