The extreme risk of breast cancer among women bearing genetic deficiencies in the p53 pathway reveals the particular importance of p53 in breast cancer susceptibility. Our laboratory has demonstrated that the activity of the p53 tumor suppressor protein in the mammary epithelium is subject to hormonal regulation. Specifically, p53 activity is compromised in mammary epithelium of nulliparous mice, but is responsive to endocrine treatments that have been shown to render the mammary epithelium resistant to carcinogenesis. Preliminary data demonstrate that treatment with both estrogen and progesterone (E+P) are required for p53-dependent responses to DNA damage in the mammary epithelium. We propose that the mammary epithelium is rendered susceptible to carcinogenesis due to impaired p53 activity during specific periods of mammary gland development, but that specific endocrine stimuli serve to activate p53 function and mitigate this risk. The experiments outlined in this proposal will define the pathways by which treatment with E+P regulate p53 function in the mammary gland.
Aim 1 : The pathways that mediate the effects of E+P on p53 activity will be examined by determining the receptors that initiate the cascade (Aim 1.1), the transcriptional targets of E+P that transduce the signal (Aim 1.2), and the enzymes that act on p53 protein to render it responsive to DNA damage-induced stress signals (Aim 1.3).
Aim 2 : Mice bearing transplants of mammary epithelium that vary in p53 status (BALB/c-Trp53+/- vs BALB/c-Trp53-/-) will be used to determine whether hormonal treatments inhibit mammary tumors by p53-dependent mechanisms.
Aim 3 : The pathways necessary for E+P-dependent activation of p53 will be examined in whole organ cultures using drug inhibitors and mammary tissue from knockout mice to identify specific targets. Breast epithelial cell lines will be used to provide higher resolution analysis of the molecular mechanisms. Based on preliminary data, the effects of retinoic acid metabolism and TGF-beta signaling will be emphasized. The results will lead to identification of cellular mechanisms that regulate p53 function in the mammary epithelium. These pathways will provide novel targets for both treatment and prevention of breast cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA095164-03S1
Application #
7261571
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Ogunbiyi, Peter
Project Start
2004-04-01
Project End
2009-02-28
Budget Start
2006-05-01
Budget End
2007-02-28
Support Year
3
Fiscal Year
2006
Total Cost
$45,899
Indirect Cost
Name
University of Massachusetts Amherst
Department
Veterinary Sciences
Type
Schools of Earth Sciences/Natur
DUNS #
153926712
City
Amherst
State
MA
Country
United States
Zip Code
01003
Tao, Luwei; Roberts, Amy L; Dunphy, Karen A et al. (2011) Repression of mammary stem/progenitor cells by p53 is mediated by Notch and separable from apoptotic activity. Stem Cells 29:119-27
Jerry, D Joseph; Dunphy, Karen A; Hagen, Mary J (2010) Estrogens, regulation of p53 and breast cancer risk: a balancing act. Cell Mol Life Sci 67:1017-23
Yan, Haoheng; Blackburn, Anneke C; McLary, S Christine et al. (2010) Pathways contributing to development of spontaneous mammary tumors in BALB/c-Trp53+/- mice. Am J Pathol 176:1421-32
Bajaj, Avinash; Miranda, Oscar R; Phillips, Ronnie et al. (2010) Array-based sensing of normal, cancerous, and metastatic cells using conjugated fluorescent polymers. J Am Chem Soc 132:1018-22
Roy, Raghunath; Jerry, D Joseph; Thayumanavan, S (2009) Virus-inspired approach to nonviral gene delivery vehicles. Biomacromolecules 10:2189-93
Bajaj, Avinash; Miranda, Oscar R; Kim, Ik-Bum et al. (2009) Detection and differentiation of normal, cancerous, and metastatic cells using nanoparticle-polymer sensor arrays. Proc Natl Acad Sci U S A 106:10912-6
Dunphy, Karen A; Blackburn, Anneke C; Yan, Haoheng et al. (2008) Estrogen and progesterone induce persistent increases in p53-dependent apoptosis and suppress mammary tumors in BALB/c-Trp53+/- mice. Breast Cancer Res 10:R43
Samanta, Bappaditya; Yan, Haoheng; Fischer, Nicholas O et al. (2008) Protein-passivated Fe(3)O(4) nanoparticles: low toxicity and rapid heating for thermal therapy. J Mater Chem 18:1204-1208
Jerry, D Joseph; Tao, Luwei; Yan, Haoheng (2008) Regulation of cancer stem cells by p53. Breast Cancer Res 10:304
Lu, Shaolei; Becker, Klaus A; Hagen, Mary J et al. (2008) Transcriptional responses to estrogen and progesterone in mammary gland identify networks regulating p53 activity. Endocrinology 149:4809-20

Showing the most recent 10 out of 11 publications