Abstract 197: Reduction in lobular but not ductal hyperplasia by the PGR inhibitor ORG33628 in a CYP19A1 overexpressing mouse model of breast cancer risk.
Authors: Dabydeen Sarah A. , Wang Weisheng , Diaz-Cruz Edgar S. , Kopelovich Levy , Glazer Robert I. , Furth Priscilla A. 
Published: August 2014

Background: The Women's Health Initiative demonstrated increased breast cancer risk in women exposed to estrogen with progesterone. Genetically engineered mice with conditional mammary epithelial cell targeted Cytochrome P45019A1 (CYP19A1/aromatase) over-expression (tet-op-CYP19A1/MMTV-rtTA mice) tested the impact of a selective progesterone receptor (PGR) inhibitor, ORG33628, on mammary hyperplasia and cancer development. This model demonstrates increased percentages of PGR+ mammary epithelial cells (MECs) cells at the hyperplastic stage and triple negative (Estrogen Receptor (ER)-, PGR-, Receptor tyrosine-protein kinase erbB-2 (HER2/neu)-) adenocarcinomas.

Purpose: Test if ORG33628 reduces mammary hyperplasia and blocks cancer formation in tet-op-CYP19A1/MMTV-rtTA mice.

Methods: Female tet-op-CYP19A1/MMTV-rtTA mice were implanted subcutaneously with a pellet containing either ORG33628 7.5mg (60-day release) or placebo at age 10m. A smaller study tested ORG33628 in CYP19A1/MMTV-rtTA/trp53+/- mice. Mice were necropsied at age 12m and mammary tissue examined to determine if ORG33628 altered lobular/ductal hyperplasia prevalence or blocked progression to hyperplastic alveolar nodules (HANs) or cancer. Immunohistochemistry (IHC) was employed to compare MEC proliferative index (PI) (Ki-67) and percentage of MECs expressing nuclear-localized ER/PGR. An uterotropic assay tested if ORG33628 blocked estrogen-induced changes in the uterus/cervix. Ovariectomized 6w old mice were implanted subcutaneously with pellets of 0.72g 17β-estradiol and either ORG33628 or placebo, necropsied 3 days later, and uterine weight, PI and ER/PGR expression compared in uterine and cervical epithelium and stroma.

Results: ORG33628 treatment reduced lobular hyperplasia prevalence (Fisher's exact, p&lt;0.05) and percentages of PGR+ MEC (9.3% to 5.2%, t-test, p&lt;0.05), but did not alter ductal hyperplasia or HAN prevalence or block cancer formation. ORG33628 reduced estrogen-induced uterine weight gain (t-test, p&lt;0.05) and PI in cervical epithelium (38.6% to 15%, t-test, p&lt;0.05) in the uterotropic assay.

Conclusions: ORG33628 reduced lobular but not ductal hyperplasia and did not prevent progression to HANs or cancer. In normal development, estrogen plays the more important role in ductal development and progesterone in lobular development paralleling the isolated impact of ORG33628 on lobular disease here. These results suggest that reducing ductal hyperplasia may be a prerequisite for cancer prevention or that reducing lobular hyperplasia at 10m in this model is too late due to the presence of triple negative cancer progenitor cells.

Support: P30CA051008, RO1CA112176, T32CA009686-15, KG080359. Content solely responsibility of authors and does not necessarily represent official NCI/NIH views.

Citation Format: Sarah A. Dabydeen, Weisheng Wang, Edgar S. Diaz-Cruz, Levy Kopelovich, Robert I. Glazer, Priscilla A. Furth. Reduction in lobular but not ductal hyperplasia by the PGR inhibitor ORG33628 in a CYP19A1 overexpressing mouse model of breast cancer risk. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 197. doi:10.1158/1538-7445.AM2013-197