title: PPARγ antagonist GW9662 induces functional estrogen receptor in mouse mammary organ culture: potential translational significance.
abstract: The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) plays a central role in regulating metabolism, including interaction with the estrogen receptor-α (ERα). Significantly, PPARγ activity can be modulated by small molecules to control cancer both in vitro and in vivo (Yin et al., Cancer Res 69:687-694, 2009). Here, we evaluated the effects of the PPARγ agonist GW7845 and the PPARγ antagonist GW9662 on DMBA-induced mammary alveolar lesions (MAL) in a mouse mammary organ culture. The results were as follows: (a) the incidence of MAL development was significantly inhibited by GW 7845 and GW 9662; (b) GW9662 but not GW7845, in the presence of estradiol, induced ER and PR expression in mammary glands and functional ERα in MAL; (c) while GW9662 inhibited expression of adipsin and ap2, GW 7845 enhanced expression of these PPARγ-response genes; and (d) Tamoxifen caused significant inhibition of GW9662 treated MAL, suggesting that GW9662 sensitizes MAL to antiestrogen treatment, presumably through rendering functional ERα and induction of PR. The induction of ERα by GW9662, including newer analogs, may permit use of anti-ER strategies to inhibit breast cancer in ER- patients.
authors.affiliation: IIT Research Institute, Chicago, IL 60616, USA. rmehta@iitri.org
authors.forename: Rajendra G
authors.initials: RG
authors.lastname: Mehta
authors.forename: Xinjian
authors.initials: X
authors.lastname: Peng
authors.forename: Sarbani
authors.initials: S
authors.lastname: Roy
authors.forename: Michael
authors.initials: M
authors.lastname: Hawthorne
authors.forename: Amit
authors.initials: A
authors.lastname: Kalra
authors.forename: Fatouma
authors.initials: F
authors.lastname: Alimirah
authors.forename: Rajeshwari R
authors.initials: RR
authors.lastname: Mehta
authors.forename: Levy
authors.initials: L
authors.lastname: Kopelovich
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene; D000813:Anilides / Q000494:pharmacology*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D004357:Drug Synergism; D004958:Estradiol / Q000502:physiology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000378:metabolism*; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D010080:Oxazoles / Q000494:pharmacology; D047495:PPAR gamma / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011230:Precancerous Conditions / Q000139:chemically induced / Q000378:metabolism; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology; D046509:Tissue Culture Techniques; D015533:Transcriptional Activation / Q000187:drug effects; D014443:Tyrosine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D016588:Anticarcinogenic Agents; D047628:Estrogen Receptor alpha; D010080:Oxazoles; D047495:PPAR gamma; D011980:Receptors, Progesterone; D013629:Tamoxifen; C401311:GW 7845; D014443:Tyrosine; D004958:Estradiol; D015127:9,10-Dimethyl-1,2-benzanthracene