Antiprogestins induce tissue remodeling in progesterone receptor isoform A (PRA)-overexpressing mammary carcinomas, increasing the concentrations of chemotherapeutic agents within the tumors.

SEQUEIRA, GONZALO; MAY, MARÍA; ROJAS, PAOLA; LAMB, CAROLINE; MOLINOLO, ALFREDO; LANARI, CLAUDIA

Rhode Island

Congreso; Gordon Research Conference: Hormone -Dependent Cancers Development and Progression; 2013

Endocrine therapies in breast cancer are designed to target the estrogen receptors alpha (ERα) and there is increasing evidence indicating that progesterone receptors (PR) are also involved modulating breast cancer growth. This suggests that antiprogestins such as mifepristone (MFP) might also be used in the treatment of this disease. However, patients with metastatic disease receive chemotherapy before endocrine treatment. Two drugs have been widely used for breast cancer treatment: paclitaxel and doxorubicin both reagents associated with serious side effects. The challenge is to increase the drug concentration within the tumor environment while decreasing their general toxicity. Based on our results in an experimental breast cancer model in which antiprogestins induced regression of mammary carcinomas overexpressing PR isoform A (PRA), we hypothesize that antiprogestins might increase the therapeutic effect of the chemotherapeutic drugs only in this selected group of tumors. PRA or PRB overexpressing murine mammary carcinomas were inoculated orthotopically into the right or left 4th mammary glands respectively. When tumors were palpable single treatments were initiated: MFP, pegylated doxorubicin liposomes (doxopeg) or albumin bound paclitaxel (abraxane) or combined treatments (MFP plus chemotherapeutic agent). We were able to show an improved effect of abraxane or doxopeg in combination with MFP only in PRA overexpressing murine mammary carcinomas. This additive effect was confirmed in T47D-YA and not in T47D-YB xenografts. We hypothesized that the tissue remodeling induced by the antiprogestin was responsible for this effect. In fact we demonstrated an increase in drug content inside the tumors overexpressing PRA as compared with those overexpressing PRB. To evaluate the microvasculature, CD31 immunostaining was performed and increased number of vessels was found in antiprogestin-treated tumors. The increased tissue remodeling found exclusively in PRA overexpressing tumors suggests that a combination of nanoparticles containing low doses of chemotherapeutic agents might be used together with the endocrine therapy to increase the efficacy of treatment.