Abstract P4-02-18: Antiprogestins as Possible Therapeutic Agents for Breast Cancer Patients Showing a High Expression of the Progesterone Receptor Isoform A

Abstract

Abstract Near 75 percent of breast cancer patients express progesterone (PR) and estrogen (ER) receptors and are potential candidates to receive an endocrine therapy. Most of the endocrine therapies available have been designed to target ER and there is not much information about PR as a therapeutic target for breast cancer treatment. However, extensive clinical and experimental evidence suggest that progestins are associated with the induction and maintenance of the neoplastic phenotype in the mammary gland. Moreover, different antiprogestins including ZK 98299, ZK 230211 and RU-486 proved to exert excellent therapeutic effects in murine mammary carcinomas from the MPA-breast cancer model which express high levels of PR with an increased PR-isoform A/PR-isoform B ratio (PR-A/PR-B) (Lanari C et al, Endocrine Related Cancer, 2009 Feb, Jun;16(2):333-50). The main goal of this study is to validate these experimental results using human breast cancer samples and to identify breast cancer patients that might benefit from an antiprogestin therapy. In the first part of this study our aim was to set up primary cultures from each breast cancer sample and to evaluate the in vitro response to antiprogestins, correlating this response with the PR-A/PR-B ratio. Tumor samples were obtained at surgery from patients diagnosed with breast cancer at the Magdalena V. de Martinez Hospital from General Pacheco and at the Rivadavia Hospital of Buenos Aires after signing the informed consent (n=70; median age 53.9 years). All tumor samples were processed by mechanical and enzymatic disaggregation and epithelial cells were purified by differential sedimentation techniques. Only 10 percent of the tumor samples succeeded in tissue culture and could be subcultured for further studies in 24 well plates. Cells were grown in culture medium in the presence of 10% fetal calf serum with or without RU-486 (10-8 M) or Tamoxifen (10-8 M). After one week of treatment, the cells were trypsinized and the total number of cells in each well was counted. Treatment with RU-486 or with Tamoxifen induced a decrease in the number of cells as compared to the controls (n=4, P<0.05). In these patients PR-A expression was the same or higher than PR-B as observed by Western Blot. Our results suggest that RU-486 might be an alternative therapy to treat breast carcinomas showing a high expression of PR-A. We still need more successful cultures in order to correlate the in vitro responsiveness with the PR isoform ratio. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-02-18.