Estrogen and progesterone regulate p53 activity in the mouse mammary epithelium through transforming growth factor β dependent pathways

2004 2004

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Abstract (summary)

Proper regulation of the p53 protein plays a critical role in suppressing tumor formation in a variety of tissues including the mammary gland. Activity of the p53 pathway is diminished in the mammary epithelium of nulliparous mice in comparison to mid-pregnant mice. P53 was shown to be regulated by estrogen and progesterone. The aim of this dissertation is to determine the molecular mechanism estrogen and progesterone utilize to sensitize p53 to radiation induced DNA damage in the mouse mammary epithelium. The first component of this work identified the minimal hormonal treatment to restore p53 activity in response to radiation. Results demonstrate that estrogen and progesterone in combination are necessary to sensitize p53 to radiation. Neither hormone alone was as effective. The effects of estrogen and progesterone were blocked by receptor antagonists. Tamoxifen in combination with progesterone was as effective as estrogen and progesterone treatments in restoring p53 responsiveness to radiation. However, the proliferation was much less in this combination than observed in treatments with estrogen and progesterone. In addition, comparison of the effects of single hormone treatments on cell cycle recruitment and p53-dependent responses revealed that theses processes were separable. The second part of this dissertation was to identify growth factors and hormones which may augment the effects of estrogen and progesterone. Results from this experiment demonstrate that transforming growth factor-β (TGF-β) is required for estrogen and progesterone to restore p53 responsiveness to radiation, as TGF-β neutralizing antibodies blocked the effects of estrogen and progesterone. However, TGF-β alone was unable to sensitize p53 to radiation. This suggests that hormone- and TGF-β-dependent pathway cooperate to restore p53 responsiveness to radiation.

Indexing (details)

Molecular biology
0307: Molecular biology
Identifier / keyword
Biological sciences; Estrogen; Mammary epithelium; Progesterone; TGF-beta; p53
Estrogen and progesterone regulate p53 activity in the mouse mammary epithelium through transforming growth factor β dependent pathways
Becker, Klaus A.
Number of pages
Publication year
Degree date
School code
DAI-B 65/01, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
Jerry, D. Joseph
University of Massachusetts Amherst
University location
United States -- Massachusetts
Source type
Dissertations & Theses
Document type
Dissertation/thesis number
ProQuest document ID
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
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