Activation of PI3K/Akt/mTOR signaling in the tumor stroma drives endocrine therapy-dependent breast tumor regression

MARÍA LAURA POLO, MARINA RIGGIO, MARÍA MAY, M. CECILIA PERRONE, M. JIMENA RODRÍGUEZ, M. STALLINGS-MANN, D. L. KAEN, M. H. FROST, M. P. GOETZ, J. C. BOUGHEY, C. LANARI, D. C. RADISKY Y VIRGINIA NOVARO.

Bariloche

Congreso; SISTAM The Third South American Spring Symposium in Signal Transduction and Molecular Medicine; 2015

Neoadjuvant endocrine-targeting therapies are employed for luminal breast carcinomas and improved efficacy could be achieved with optimal use of other pathway targeting agents. Using pre-clinical models of ductal breast carcinomas, we identified a stromal reaction that starts within hours after treatment and that is characterized by an increase in smooth muscle actin (αSMA), neovascularization (CD31) and intratumoral infiltration of immune cells. This endocrine therapy-associated stromal reaction requires activation of the PI3K/Akt/mTOR pathway, as evidenced by phosphorylation of ribosomal protein S6 (pS6) detected by specific protein expression by immunohistochemistry and western blot. Using the medroxyprogesterone acetate (MPA)-induced mouse models of breast cancer we found that tumors with high intrinsic parenchymal-PI3K/Akt activity responded well to a combination of endocrine and PI3K/Akt/mTOR inhibitors, due to reduced proliferation and increased apoptosis of tumor cells. However, tumors with low intrinsic parenchymal-PI3K/Akt responded more poorly to the combination therapy than to the endocrine therapy alone, due to inhibition of the tumor-regressive stromal reaction. Consistently, when Akt was constitutively activated in T47D and IBH-6 human breast cancer cells, they became more sensitive to PI3K/mTOR inhibitors both in culture and in xenografts, while cells with basal levels of Akt showed a better response to endocrine therapy. Finally, we found that the clinical response of breast cancer patients undergoing neoadjuvant endocrine therapy is associated with an active stromal response with high αSMA, CD31 and pS6 levels. Together, our findings suggest a differential role of PI3K/Akt/mTOR pathway on stromal reaction and tumor regression after endocrine therapy, and that pS6 is a biomarker to early distinguish which tumors would benefit from the incorporation of PI3K/Akt/mTOR inhibitors for neoadjuvant therapy.