Accession Number:

ADA429003

Title:

Functional Estrogen Deprivation by activating the Orphan Nuclear Receptor PXR

Descriptive Note:

Final rept. 1 Aug 2003-31 Jul 2004

Corporate Author:

PITTSBURGH UNIV PA

Personal Author(s):

Report Date:

2004-08-01

Pagination or Media Count:

36.0

Abstract:

Estrogens are required for mammary epithelial proliferation and are prerequisite for breast cancer formation. Accordingly, strategies to down-regulate estrogen activity have been proven effective to treat and prevent breast cancer. A major pathway to deactivate estrogens is through estrogen sulfation mediated by the phase II sulfotransferases SULT. SULT is expressed in normal mammary epithelial cells but its expression and activities are significantly lower in many breast cancer cells, suggesting that down-regulation of SULT may led to unchecked estrogen stimulation and cancerous transformation. The expression of sulfotransferase is regulated by orphan nuclear receptor PXR. We hypothesize that the lower SULT activity in breast cancer cells is due to lower expression and activation of the PXR receptor. Activation of PXR by chemical or genetic means will induce the expression of SULT, which in turn facilitates estrogen deactivation and inhibits estrogen-dependent breast cancer cell growth. The traditional antiestrogenic agents such as tamoxifen, though effective, are known to have untoward clinical side effects. It is anticipated that development of PXR activating and ER neutral agents may represent a novel strategy to functionally deprive estrogen activity and to treat and prevent breast cancers.

Subject Categories:

  • Medicine and Medical Research

Distribution Statement:

APPROVED FOR PUBLIC RELEASE