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
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.
| Medienart: |
Artikel |
|---|
| Erscheinungsjahr: |
2005 |
|---|---|
| Erschienen: |
2005 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:65 |
|---|---|
| Enthalten in: |
Cancer research - 65(2005), 24 vom: 15. Dez., Seite 11762-70 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Safi, Rachid [VerfasserIn] |
|---|
| Anmerkungen: |
Date Completed 23.02.2006 Date Revised 03.12.2018 published: Print Citation Status MEDLINE |
|---|
| Förderinstitution / Projekttitel: |
|
|---|
| PPN (Katalog-ID): |
NLM159587387 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM159587387 | ||
| 003 | DE-627 | ||
| 005 | 20231223084427.0 | ||
| 007 | tu | ||
| 008 | 231223s2005 xx ||||| 00| ||eng c | ||
| 028 | 5 | 2 | |a pubmed24n0532.xml |
| 035 | |a (DE-627)NLM159587387 | ||
| 035 | |a (NLM)16357189 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Safi, Rachid |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a 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 |
| 264 | 1 | |c 2005 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ohne Hilfsmittel zu benutzen |b n |2 rdamedia | ||
| 338 | |a Band |b nc |2 rdacarrier | ||
| 500 | |a Date Completed 23.02.2006 | ||
| 500 | |a Date Revised 03.12.2018 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, U.S. Gov't, Non-P.H.S. | |
| 650 | 7 | |a Antineoplastic Agents |2 NLM | |
| 650 | 7 | |a DNA-Binding Proteins |2 NLM | |
| 650 | 7 | |a Estrogens |2 NLM | |
| 650 | 7 | |a Heat-Shock Proteins |2 NLM | |
| 650 | 7 | |a NR5A2 protein, human |2 NLM | |
| 650 | 7 | |a Nr5a2 protein, mouse |2 NLM | |
| 650 | 7 | |a PPARGC1A protein, human |2 NLM | |
| 650 | 7 | |a Peptide Fragments |2 NLM | |
| 650 | 7 | |a Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha |2 NLM | |
| 650 | 7 | |a Receptors, Cytoplasmic and Nuclear |2 NLM | |
| 650 | 7 | |a Retinoid X Receptor alpha |2 NLM | |
| 650 | 7 | |a Transcription Factors |2 NLM | |
| 650 | 7 | |a Alitretinoin |2 NLM | |
| 650 | 7 | |a 1UA8E65KDZ |2 NLM | |
| 650 | 7 | |a Tretinoin |2 NLM | |
| 650 | 7 | |a 5688UTC01R |2 NLM | |
| 650 | 7 | |a Aromatase |2 NLM | |
| 650 | 7 | |a EC 1.14.14.1 |2 NLM | |
| 700 | 1 | |a Kovacic, Agnes |e verfasserin |4 aut | |
| 700 | 1 | |a Gaillard, Stéphanie |e verfasserin |4 aut | |
| 700 | 1 | |a Murata, Yoko |e verfasserin |4 aut | |
| 700 | 1 | |a Simpson, Evan R |e verfasserin |4 aut | |
| 700 | 1 | |a McDonnell, Donald P |e verfasserin |4 aut | |
| 700 | 1 | |a Clyne, Colin D |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Cancer research |d 1945 |g 65(2005), 24 vom: 15. Dez., Seite 11762-70 |w (DE-627)NLM000001740 |x 1538-7445 |7 nnns |
| 773 | 1 | 8 | |g volume:65 |g year:2005 |g number:24 |g day:15 |g month:12 |g pages:11762-70 |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 65 |j 2005 |e 24 |b 15 |c 12 |h 11762-70 | ||