The expression of estrogen receptor-alpha (ERa) is critical for establishing the hormone responsive phenotype of breast cancers. Functional promoter analysis and hypersensitive site mapping identified the AP2y transcription factor as a regulator of ERa expression and confirmed the location of AP2 regulatory sites in the human ERa gene promoter. Eliminating AP2y expression in ERa-positive cells using siRNA significantly down-regulates the expression of ERa and ERa-target genes. We conclude that AP2y is a key regulator of ERa expression in hormone responsive breast cancer cells. Epigenetic alterations involving methylation and histone acetylation have also been shown to contribute to the control of ERa gene expression. We hypothesize that epigenetic changes involving the AP2 regulatory element may provide an additional mechanism to regulate expression from the ERa promoter. Furthermore, we have identified an interaction between AP2 factors and the tumor suppressor protein p53 and there is substantial evidence showing that overexpression of p53 is capable of inhibiting the transcriptional activity of AP2. Hence, the interaction between AP2 factors and p53 represents another potential mechanism regulating the expression of ERa and may explain the finding that breast cancers with p53 overexpression are usually ERa-negative. Herein we propose to define the mechanisms regulating AP2-mediated activation of ERa and to determine the physiologic processes of hormone response controlled by AP2y. To accomplish this goal we propose to analyze the parameters of hormone response controlled by AP2y in MCF7 cells. We will define the functional domains of AP2 factors that are necessary for regulation of ERa. Using cell models of ERa repression and reactivation, we will determine if epigenetic alterations of the AP2 regulatory region contribute to control of ERa expression. We will investigate the mechanisms of p53-mediated repression of ERa by determining if p53 alters AP2y activity or chromatin interaction. The role of p53 in regulating ERa will be investigated by examining p53 alleles recovered from breast cancers for mutationsthat disrupt the AP2-interaction domain. We will define residues that are critical for the interaction between AP2 and p53 and generate antagonists as a prelude to developing a specific inhibitor of the AP2-p53 interaction. In the future it may be possible to develop a novel therapeutic to induce hormone response in breast cancers by specifically targeting the AP2 pathway.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA109294-04
Application #
7535261
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Sathyamoorthy, Neeraja
Project Start
2006-02-01
Project End
2010-12-31
Budget Start
2009-01-01
Budget End
2009-12-31
Support Year
4
Fiscal Year
2009
Total Cost
$231,383
Indirect Cost
Name
University of Iowa
Department
Surgery
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Cyr, A R; Kulak, M V; Park, J M et al. (2015) TFAP2C governs the luminal epithelial phenotype in mammary development and carcinogenesis. Oncogene 34:436-44
Bogachek, Maria V; Park, Jung Min; De Andrade, James P et al. (2015) A novel animal model for locally advanced breast cancer. Ann Surg Oncol 22:866-73
Spanheimer, Philip M; Lorenzen, Allison W; De Andrade, James P et al. (2015) Receptor Tyrosine Kinase Expression Predicts Response to Sunitinib in Breast Cancer. Ann Surg Oncol 22:4287-94
Bogachek, Maria V; De Andrade, James P; Weigel, Ronald J (2015) Regulation of epithelial-mesenchymal transition through SUMOylation of transcription factors. Cancer Res 75:11-5
Park, J M; Wu, T; Cyr, A R et al. (2015) The role of Tcfap2c in tumorigenesis and cancer growth in an activated Neu model of mammary carcinogenesis. Oncogene 34:6105-14
Spanheimer, Philip M; Park, Jung-Min; Askeland, Ryan W et al. (2014) Inhibition of RET increases the efficacy of antiestrogen and is a novel treatment strategy for luminal breast cancer. Clin Cancer Res 20:2115-25
Spanheimer, Philip M; Cyr, Anthony R; Gillum, Matthew P et al. (2014) Distinct pathways regulated by RET and estrogen receptor in luminal breast cancer demonstrate the biological basis for combination therapy. Ann Surg 259:793-9
Bogachek, Maria V; Chen, Yizhen; Kulak, Mikhail V et al. (2014) Sumoylation pathway is required to maintain the basal breast cancer subtype. Cancer Cell 25:748-61
Spanheimer, Philip M; Carr, Jennifer C; Thomas, Alexandra et al. (2013) The response to neoadjuvant chemotherapy predicts clinical outcome and increases breast conservation in advanced breast cancer. Am J Surg 206:2-7
Spanheimer, Philip M; Woodfield, George W; Cyr, Anthony R et al. (2013) Expression of the RET proto-oncogene is regulated by TFAP2C in breast cancer independent of the estrogen receptor. Ann Surg Oncol 20:2204-12

Showing the most recent 10 out of 18 publications