Abstract

Our research focuses on studies to delineate the function of nuclear receptor coactivators in the development of mammary gland and breast cancer. Peroxisome proliferator-activated receptor (PPAR) binding protein (PBP, also known as TRAP220/DRIP205/MED1) is one of the coactivators we isolated a few years ago. PBP was implicated in the breast cancer tumorigenesis by our finding that it is overexpressed and amplified in a proportion of breast cancers. The studies supported by this grant over the past five years demonstrated that PBP is essential for the normal mammary gland development. Conditional mammary null mouse model revealed that loss of PBP leads to severely retarded ductal elongation during puberty and lobuloalveolar proliferation during pregnancy and lactation. The impaired mammary stem/progenitor cells, due to PBP gene disruption, were found to be responsible for this phenotype. Studies with mammary cell lines derived from the genetically modified mice demonstrated that PBP is also involved in the growth of cancer stem cells. Furthermore, the development of tamoxifen resistance requires PBP. In addition, a PBP isoform was found to be markedly overexpressed in breast cancer and the overexpression could increase the number of cancer stem cells. Based on these results, we hypothesize that PBP is essential for the growth and differentiation of both normal and cancer mammary stem/progenitor cells. By functioning as a coactivator of several transcription factors including estrogen receptor, PBP serves as a central coordinator to integrate multiple signaling pathways which regulate mammary stem/progenitor cells. The objectives of the proposed studies are to delineate the mechanisms by which PBP regulates the growth and differentiation of mammary stem (normal and cancer) cells.
Our specific aims are to: 1). determine the mechanism by which PBP regulates the maintenance, proliferation and differentiation of mammary stem/ progenitor cells;2). define the role of PBP in the proliferation and differentiation of cancer stem cells;3). investigate the role of PBP in the development of anti-estrogen resistance. Our proposed studies will generate new information on the biology of mammary stem (normal and cancer) cells, which could provide novel avenues for breast cancer prevention and treatment.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA088898-08
Application #
7617852
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Sathyamoorthy, Neeraja
Project Start
2001-02-01
Project End
2011-03-31
Budget Start
2009-06-01
Budget End
2011-03-31
Support Year
8
Fiscal Year
2009
Total Cost
$226,500
Indirect Cost

  Institution

Name
Northwestern University at Chicago
Department
Pathology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611

  Publications

Qi, Jin; Huo, Lei; Zhu, Yiwei Tony et al. (2014) Absent, small or homeotic 2-like protein (ASH2L) enhances the transcription of the estrogen receptor ? gene through GATA-binding protein 3 (GATA3). J Biol Chem 289:31373-81
Qi, Chao; Zhu, Yiwei Tony; Hu, Liping et al. (2009) Identification of Fat4 as a candidate tumor suppressor gene in breast cancers. Int J Cancer 124:793-8
Hu, Liping; Zhu, Yiwei Tony; Qi, Chao et al. (2009) Identification of Smyd4 as a potential tumor suppressor gene involved in breast cancer development. Cancer Res 69:4067-72
Zhu, Yiwei Tony; Jia, Yuzhi; Hu, Liping et al. (2009) Peroxisome-proliferator-activated receptor-binding protein (PBP) is essential for the growth of active Notch4-immortalized mammary epithelial cells by activating SOX10 expression. Biochem J 425:435-44
Zhu, Yiwei Tony; Hu, Liping; Qi, Chao et al. (2009) PRIP promotes tumor formation through enhancing serum-responsive factor-mediated FOS expression. J Biol Chem 284:14485-92
Mo, Rigen; Tony Zhu, Yiwei; Zhang, Zhongyi et al. (2007) GAS6 is an estrogen-inducible gene in mammary epithelial cells. Biochem Biophys Res Commun 353:189-94
Zhu, Yiwei Tony; Qi, Chao; Hu, Liping et al. (2007) Efficient generation of random chromosome deletions. Biotechniques 42:572, 574, 576
Mo, Rigen; Rao, Sambasiva M; Zhu, Yi-Jun (2006) Identification of the MLL2 complex as a coactivator for estrogen receptor alpha. J Biol Chem 281:15714-20
Jia, Yuzhi; Qi, Chao; Zhang, Zhongyi et al. (2005) Peroxisome proliferator-activated receptor-binding protein null mutation results in defective mammary gland development. J Biol Chem 280:10766-73
Qi, Chao; Zhu, Yiwei Tony; Chang, Jeffrey et al. (2005) Potentiation of estrogen receptor transcriptional activity by breast cancer amplified sequence 2. Biochem Biophys Res Commun 328:393-8

Showing the most recent 10 out of 17 publications