Early tumor regression after endocrine and kinase inhibitor therapy in an experimental model of breast cancer

POLO MARIA LAURA; MARINA RIGGIO; CLAUDIA LANARI; VIRGINIA NOVARO

Washington

Congreso; 104 th American Association for Cancer Research Anual Meeting; 2013

AACR

More than 70% of breast cancers express estrogen and progesterone receptors (ER and PR), and are thus susceptible to adjuvant endocrine therapy. Treatments for these patients are mainly focused on blocking ER function at multiple levels. In the last few years, evidence has linked progestin to breast cancer pathogenesis. According to that, PR would be a valid target for breast cancer therapy. In addition, up to 40% of hormone-receptor positive breast tumors have PI3K activating mutations, and then PI3K/AKT inhibition is becoming a new approach for breast cancer treatment. The aim of this work was to study early stages of tumor regression in an experimental model of breast cancer. We tested the effect of an antiprogestin and a PI3K inhibitor for 48 hs, alone or in combination. We used the medroxyprogesterone acetate (MPA)-induced breast cancer model. Tumors of this model express high levels of ER and PR. Initially, they are MPA-dependent, but after a few passages MPA-independent variants appear spontaneously. These variants may respond to an endocrine therapy or may progress to a hormonal resistant phenotype. We have previously demonstrated that the MPA-independent variant C4-HI regresses after 48 hs administration of the antiprogestin Mifepristone (MFP, 12 mg/kg/day) or the PI3K inhibitor Wortmannin (WN, 1 mg/kg/day), displaying an increase in ductal differentiation. We now explored the mechanisms involved in these inhibitory effects. Proliferation of tumor cells, determined as mitotic and Ki67 indexes, is reduced (p