Abstract/Details

The role of ERα, ERβ and phytoestrogens from soy in p53-mediated response to DNA damage in mammary epithelium


2009 2009

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Abstract (summary)

Estrogenic compounds can stimulate proliferation of the mammary epithelium, but also potentiate the activity of the p53 tumor suppressor protein. These contradictory activities of estrogenic compounds in mammary tissues may be mediated through activation of two estrogen receptor (ER) subtypes, ERα and ERβ. The following experiments were conducted to examine the roles of these receptors in regulating p53 activity in the mammary epithelium in vivo and in vitro.

Selective agonist for ERα (PPT) and ERβ (DPN) were compared with 17β-estradiol to examine the roles of ERα and ERβ in potentiating p53 activity, radiation-induced apoptosis and proliferation in ovariectomized mice. DPN was sufficient to potentiate p53-dependent apoptosis in the mammary epithelium following irradiation without inducing proliferation. DPN was also 2.5-fold more potent in stimulating expression of Egr1 , a modulator of p53 activity. Introduction of ERβ into MCF-7 cells increased in the transcriptional activity of p53. As radiation-induced apoptosis was diminished in mice lacking ERβ (BERKO) mice, ERβ appears necessary for optimal activity of p53 in the mammary epithelium. The ability of DPN to maximally stimulate responsiveness of p53 to ionizing radiation in the absence of proliferation suggests that ERβ agonists may be an effective adjuvant therapy.

Phytoestrogens are estrogenic compounds that are abundant in soy-based products, a key component in Asian diet associated with reduced breast cancer incidence in Asian women, and are preferential ligands for ERβ. However, the effects of soy differ greatly depending on the form and doses administered. Therefore, the effects of water-soluble extracts of non-fermented and fermented soy (NFSE and FSE, respectively) were compared. At physiological relevant doses both NFSE and FSE inhibited proliferation of cell lines from normal breast epithelium (76N-TERT) and breast cancers (21MT-1,MDA-MB-231). The FSE also increased the tumor-free survival of mice bearing xenografts of MDA-MB-231 cells. However, these effects of soy extracts were independent of both p53 and ERα. As both p53 and ERα are commonly lost in breast tumors, the pathways by which soy extracts antagonize tumor growth could provide valuable therapeutic targets for the treatment and prevention of breast tumors.

Indexing (details)


Subject
Molecular biology;
Cellular biology
Classification
0307: Molecular biology
0379: Cellular biology
Identifier / keyword
Biological sciences; Breast cancer; DNA damage; Estrogen receptors; Mammary tumors; Phytoestrogens; p53
Title
The role of ERα, ERβ and phytoestrogens from soy in p53-mediated response to DNA damage in mammary epithelium
Author
Roman Perez, Erick
Number of pages
138
Publication year
2009
Degree date
2009
School code
0118
Source
DAI-B 70/09, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
ISBN
9781109352160
Advisor
Jerry, D. Joseph
Committee member
Kim, Young-Cheul; Petersen, Sandra L.; Smith Schneider, Sallie
University/institution
University of Massachusetts Amherst
Department
Molecular & Cellular Biology
University location
United States -- Massachusetts
Degree
Ph.D.
Source type
Dissertations & Theses
Language
English
Document type
Dissertation/Thesis
Dissertation/thesis number
3372274
ProQuest document ID
304926269
Copyright
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
http://search.proquest.com/docview/304926269
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