Author: Alexi, Xanthippi ; Zwart, Wilbert ; van der Burg, Eline ; Bouwman, Peter ; van de Ven, Marieke ; Klarenbeek, Sjoerd ; Dijcks, Fred ; Jonkers, Jos ; Liu, Xiaoling

AbstractHereditary breast cancers in BRCA1 mutation carriers are mostly estrogen receptor α (ERα)‐negative and progesterone receptor (PR)‐negative; however, hormone depletion via bilateral oophorectomy does result in a marked reduction in breast cancer risk, suggesting that BRCA1‐associated breast tumorigenesis is dependent on hormone signaling. We used geneticaly engineered mouse models to determine the individual influences of ERα and PR signaling on the development of BRCA1‐deficient breast cancer. In line with the human data, BRCA1‐deficient mouse mammary tumors are ERα‐negative, and bilateral ovariectomy leads to abrogation of mammary tumor development. Hormonal replacement experiments in ovariectomized mice showed that BRCA1‐deficient mammary tumor formation is promoted by estrogen but not by progesterone. In line with these data, mammary tumorigenesis was significantly delayed by the selective ERα downregulator fulvestrant, but not by the selective PR antagonist Org33628. Together, our results illustrate that BRCA1‐associated tumorigenesis is dependent on estrogen signaling rather than on progesterone signaling, and call into question the utility of PR antagonists as a tumor prevention strategy for BRCA1 mutation carriers. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

01 Sep 2013·SteroidsQ4 · MEDICINE

Synthesis and antiprogestational properties of novel 17-fluorinated steroids

Q4 · MEDICINE

Article

Author: Shylesh S. Bhaskaran ; Klaus Nickisch ; Hareesh B. Nair ; Narkunan Kesavaram ; Shao-Qing Shi ; Robert Garfield ; Sandra L. Grimm ; Baishakhi Das ; Dean P. Edwards

Progesterone receptor (PR) plays a key role in reproductive functions, and compounds that inhibit progesterone action (antiprogestins) have potential use in the treatment of estrogen- and progesterone-dependent diseases, including uterine leiomyomas and breast cancer. In the present study, we chemically synthesized novel 17-fluorinated steroids and evaluated the cytotoxicity profiles of these compounds in T47D breast cancer cells compared to the activity of known antiprogestins, including ZK230 211, RU-486, CDB2914, CDB4124 and ORG33628. We analyzed in vitro receptor-binding assays and PR-transactivation assays to establish the antiprogestational activity of these molecules. The representative antiprogestin EC304 was found to inhibit in vitro tumorigenicity in a dose-dependent fashion in T47D cells by a colony formation assay at 1 and 10nM concentrations. The potent in vivo antiprogestational activity of EC304 was also demonstrated in an antinidation assay for the interruption of early pregnancy in rats. The strong antiprogestational activity and absence of antiglucocorticoid activity in EC compounds may demonstrate their utility in the treatment of leiomyoma, endometriosis and breast cancer.

01 Sep 2011·REPRODUCTIONQ3 · BIOLOGY

Regulation of prolactin secretion during the estrus in rats: possible role of glucocorticoids

Q3 · BIOLOGY

Article

Author: de Di Nasso, Florencia E. G. ; Maselli, Maria E. ; Caron, Ruben W. ; Lopez-Fontana, Constanza M. ; Telleria, Carlos M.

Mifepristone (MIF) administration to cycling rats at proestrus induces hypersecretion of prolactin (PRL) at the following estrus. We aimed to assess whether this effect is due to the antiprogesterone or antiglucocorticoid action of MIF and to help underscore the nature of the circulating hormone(s) regulating PRL secretion at estrus. Female cycling rats in proestrus were treated with vehicle; the progesterone (Pg) and glucocorticoid receptor antagonists, MIF (5 mg/kg) or ORG-33628 (5 mg/kg); the glucocorticoid agonist dexamethasone (DEX; 27 mg/kg)±MIF; or the inhibitor of steroid synthesis aminoglutethimide (AG; 150 mg/kg)±MIF. The animals' blood was sampled the same day at 1800 h and at 1800 h of the following day to assess for circulating PRL and Pg levels. To distinguish antiglucocorticoid from antiprogesterone effects of MIF, we administered a highly specific neutralizing antibody against Pg. None of the antagonists modified serum PRL values at proestrus but increased PRL levels at estrus. DEX decreased the secretion of PRL at proestrus, yet the effect was entirely blocked by MIF. Furthermore, DEX decreased PRL at estrus in a MIF-reversible manner, suggesting that adrenal corticoids during proestrous may regulate PRL secretion at estrus. AG increased PRL secretion at estrus, whereas its association with MIF produced an even higher response. PRL concentration at estrus was not modified by the antiprogesterone antibody, suggesting that the effect of MIF is a consequence of its antiglucocorticoid effect and not due to its antiprogesterone properties. In conclusion, PRL secretion in the afternoon of the estrus is most likely regulated by glucocorticoids through an inhibitory action.

100 Deals associated with Org-33628

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Indication	Highest Phase	Country/Location	Organization	Date
Contraception	Phase 2	-	Organon & Co.	-
Pregnancy	Phase 2	NL	Organon & Co.	-

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