Estrogen is a critical regulator of breast growth, development, and transformation, and blocking estrogen- induced activation of the estrogen receptor (ER) has been the most successful way to treat and prevent breast cancer. However, despite the impressive activity of anti-estrogen and aromatase inhibitor drugs, currently available hormonal agents are unable to cure or prevent breast cancer in all women. We propose that through a better understanding of the molecules that participate with estrogen in regulating breast cell growth and transformation, it will be possible to develop molecularly targeted agents to more effectively prevent and treat breast cancer. Although the estrogen receptors have been well described, the molecular mechanism by which estrogen regulates breast cell growth and transformation is not fully understood. The "classical" pathway by which estrogen and the estrogen receptors activate gene expression is well known. However, recent studies have demonstrated that estrogen also regulates growth through other "non-classical" pathways by activating cytoplasmic kinase cascades and other transcription factors through transcription factor crosstalk. We and others have shown that a primary factor activated by estrogen is the AP-1 transcription factor, a critical regulator of breast cell growth and invasion and a marker of poor prognosis in women with breast cancer. We now hypothesize that the crosstalk between estrogen receptors and AP-1 transcription factors is essential for breast cell growth and transformation, and that this pathway can be targeted for the prevention and treatment of breast cancer. We propose to investigate how activation of the AP-1 transcription factor by estrogen controls expression of estrogen-regulated genes, mammary tumor development, and breast cancer growth. Specifically, we will: (1) investigate the molecular mechanism by which ER and AP-1 proteins collaborate to induce expression of critical growth regulatory genes in breast cells;(2) determine whether in vivo AP-1 blockade prevents oncogene-induced breast cancer;and (3) determine whether inhibition of the AP-1 transcription factor will suppress the growth of established breast cancers and enhance the effect of hormonal- and chemo-therapies. These studies will have a major public health benefit by providing the foundation and rationale to develop agents capable of disrupting this collaboration between AP-1 and ER, thus effectively preventing all breast cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA123246-05
Application #
8029589
Study Section
Special Emphasis Panel (ZRG1-MONC-U (01))
Program Officer
Sathyamoorthy, Neeraja
Project Start
2007-06-06
Project End
2013-01-31
Budget Start
2011-02-01
Budget End
2013-01-31
Support Year
5
Fiscal Year
2011
Total Cost
$291,194
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
None
Type
Schools of Medicine
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Wang, Chunyu; Uray, Ivan P; Mazumdar, Abhijit et al. (2012) SLC22A5/OCTN2 expression in breast cancer is induced by estrogen via a novel intronic estrogen-response element (ERE). Breast Cancer Res Treat 134:101-15
Wang, Chunyu; Mayer, Julie Ann; Mazumdar, Abhijit et al. (2012) The rearranged during transfection/papillary thyroid carcinoma tyrosine kinase is an estrogen-dependent gene required for the growth of estrogen receptor positive breast cancer cells. Breast Cancer Res Treat 133:487-500
Wang, Chunyu; Mayer, Julie Ann; Mazumdar, Abhijit et al. (2011) Estrogen induces c-myc gene expression via an upstream enhancer activated by the estrogen receptor and the AP-1 transcription factor. Mol Endocrinol 25:1527-38
Howe, Louise R; Brown, Powel H (2011) Targeting the HER/EGFR/ErbB family to prevent breast cancer. Cancer Prev Res (Phila) 4:1149-57
Shen, Qiang; Uray, Ivan P; Li, Yuxin et al. (2008) Targeting the activator protein 1 transcription factor for the prevention of estrogen receptor-negative mammary tumors. Cancer Prev Res (Phila) 1:45-55