Antiprogestin responsiveness of a human breast cancer xenograft model overexpressing progesterone receptors isoforms A (PRA) or B (PRB)

GONZALO R. SEQUEIRA, SR., PAOLA ROJAS, MARIA MAY, CLAUDIA LANARI.

Washington

Congreso; Annual Meeting of the American Association of Cancer Research; 2013

AACR

Endocrine therapies in breast cancer are designed to target directly or indirectly the estrogen receptors alpha (ERα). There is increasing evidence indicating that progesterone receptors (PR) are involved as ERα modulating breast cancer growth. Antiprogestins had been used in clinical trials in patients who have failed to other therapies; however, the results were not very clear. Our laboratory has developed an experimental murine model of breast cancer in which mammary carcinomas, expressing ER and PR, transit through different stages of hormone dependency. We demonstrated using this model, that only tumors with higher levels of PRA than PRB were those responsive to antiprogestin treatment. Moreover, the antiprogestin mifepristone (MFP) was able to stimulate the growth of tumors overexpressing PRB. The aim of this study was to move into a human in mouse scenario in order to test our hypothesis postulating that only breast cancer patients with higher levels of PRA than PRB are susceptible to MFP treatment. T47D-YA and T47D-YB kindly provided by Dr. K. Horwitz (University of Colorado, Denver), were inoculated sc with matrigel into the right and left flanks respectively of female NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice (5/group; 3 experiments) that have been implanted one week before with a sc 17-β-estradiol pellet (0.5mg). After 10 days, when tumors reached a size greater than 20 mm2, the mice were treated with silastic or MFP (6 mg) pellets sc. In other experiments MFP was administered as daily injections of 10 mg/kg/body weight. Animals were followed for 2 weeks. A significant decrease in tumor size was only registered in T47D-YA tumors treated with MFP (p<0.05). Interestingly the T47D-YB tumors growing in the contralateral flank of the same mice increased their size with MFP treatment. They reached a size even larger than control -YB tumors (p<0.05). T47D-YA tumors showed nuclear MYC and Cyclin D1 staining whereas a cytoplasmic staining was observed in MFP-treated tumors 72 hours after treatment (immunohistochemistry). Conversely, an intense nuclear staining of both proteins was observed in T47D-YB tumors growing with MFP treatment. It can be concluded that in this human in mouse model, a specific inhibitory effect of MFP is only obtained in xenografts expressing PRA, while a stimulatory effect may be achieved in tumors expressing only PRB. These results are in agreement with our data in murine tumors and as a whole suggest that antiprogestins may be excellent therapeutic tools for breast cancer patients with higher levels of PRA than PRB.