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Coactivation of liver receptor homologue-1 by peroxisome proliferator-activated receptor gamma coactivator-1alpha on aromatase promoter II and its inhibition by activated retinoid X receptor suggest a novel target for breast-specific antiestrogen therapy.

Publication ,  Journal Article
Safi, R; Kovacic, A; Gaillard, S; Murata, Y; Simpson, ER; McDonnell, DP; Clyne, CD
Published in: Cancer Res
December 15, 2005

Aromatase inhibitors target the production of estrogen in breast adipose tissue, but in doing so, also decrease estrogen formation in bone and other sites, giving rise to deleterious side effects, such as bone loss and arthralgia. Thus, it would be clinically useful to selectively inhibit aromatase production in breast. In this regard, we have determined that the orphan nuclear receptor liver receptor homologue-1 (LRH-1) is a specific transcriptional activator of aromatase gene expression in human breast preadipocytes but not in other tissues of postmenopausal women. In this study, we show that the coactivator peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) is a physiologically relevant modulator of LRH-1, and that its transcriptional activity can be inhibited effectively using receptor-interacting peptide antagonists that prevent PGC-1alpha recruitment. Interestingly, we note that all of these peptides also interact in an agonist-dependent manner with retinoid X receptor alpha (RXRalpha), suggesting that these two receptors may compete for limiting cofactors within target cells. In support of this hypothesis, we show that 9-cis-retinoic acid, acting through RXR, inhibits both the basal and PGC-1alpha-induced transcriptional activity of LRH-1. The importance of this finding was confirmed by showing that LRH-1-dependent, PGC-1alpha-stimulated regulation of aromatase gene expression in primary human breast preadipocytes was effectively suppressed by RXR agonists. We infer from these data that LRH-1 is a bona fide target whose inhibition would selectively block aromatase expression in breast, while sparing other sites of expression.

Duke Scholars

Published In

Cancer Res

DOI

ISSN

0008-5472

Publication Date

December 15, 2005

Volume

65

Issue

24

Start / End Page

11762 / 11770

Location

United States

Related Subject Headings

  • Tretinoin
  • Transcription, Genetic
  • Transcription Factors
  • Retinoid X Receptor alpha
  • Receptors, Cytoplasmic and Nuclear
  • Promoter Regions, Genetic
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Peptide Fragments
  • Oncology & Carcinogenesis
  • Mice
 

Citation

APA
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ICMJE
MLA
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Safi, R., Kovacic, A., Gaillard, S., Murata, Y., Simpson, E. R., McDonnell, D. P., & Clyne, C. D. (2005). Coactivation of liver receptor homologue-1 by peroxisome proliferator-activated receptor gamma coactivator-1alpha on aromatase promoter II and its inhibition by activated retinoid X receptor suggest a novel target for breast-specific antiestrogen therapy. Cancer Res, 65(24), 11762–11770. https://doi.org/10.1158/0008-5472.CAN-05-2792
Safi, Rachid, Agnes Kovacic, Stéphanie Gaillard, Yoko Murata, Evan R. Simpson, Donald P. McDonnell, and Colin D. Clyne. “Coactivation of liver receptor homologue-1 by peroxisome proliferator-activated receptor gamma coactivator-1alpha on aromatase promoter II and its inhibition by activated retinoid X receptor suggest a novel target for breast-specific antiestrogen therapy.Cancer Res 65, no. 24 (December 15, 2005): 11762–70. https://doi.org/10.1158/0008-5472.CAN-05-2792.

Published In

Cancer Res

DOI

ISSN

0008-5472

Publication Date

December 15, 2005

Volume

65

Issue

24

Start / End Page

11762 / 11770

Location

United States

Related Subject Headings

  • Tretinoin
  • Transcription, Genetic
  • Transcription Factors
  • Retinoid X Receptor alpha
  • Receptors, Cytoplasmic and Nuclear
  • Promoter Regions, Genetic
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Peptide Fragments
  • Oncology & Carcinogenesis
  • Mice