Activation of PI3K/Akt/mTOR signaling in the tumor stroma drives endocrine therapy-dependent breast tumor regression
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María Laura Polo1, Marina Riggio1, María May1, María Jimena Rodríguez1, María Cecilia Perrone1, Melody Stallings-Mann2, Diego Kaen3, Marlene Frost4, Matthew Goetz4, Judy Boughey5, Claudia Lanari1, Derek Radisky2, Virginia Novaro1
1Instituto de Biología y Medicina Experimental, Protein Kinases and Cancer Laboratory, Buenos Aires, Argentina
2Mayo Clinic Comprehensive Cancer Center, Department of Cancer Biology, Jacksonville, FL, USA
3Centro Oncológico Riojano Integral, Medical Oncology, La Rioja, Argentina
4Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA
5Department of Surgery, Mayo Clinic, Rochester, MN, USA
Virginia Novaro, e-mail: [email protected]
Keywords: tumor stroma, neoadjuvant endocrine therapy, PI3K/Akt pathway, breast cancer
Received: April 21, 2015 Accepted: May 27, 2015 Published: June 08, 2015
Improved efficacy of neoadjuvant endocrine-targeting therapies in luminal breast carcinomas could be achieved with optimal use of pathway targeting agents. In a mouse model of ductal breast carcinoma we identify a tumor regressive stromal reaction that is induced by neoadjuvant endocrine therapy. This reparative reaction is characterized by tumor neovascularization accompanied by infiltration of immune cells and carcinoma-associated fibroblasts that stain for phosphorylated ribosomal protein S6 (pS6), downstream the PI3K/Akt/mTOR pathway. While tumor variants with higher PI3K/Akt/mTOR activity respond well to a combination of endocrine and PI3K/Akt/mTOR inhibitors, tumor variants with lower PI3K/Akt/mTOR activity respond more poorly to the combination therapy than to the endocrine therapy alone, associated with inhibition of stromal pS6 and the reparative reaction. In human breast cancer xenografts we confirm that such differential sensitivity to therapy is primarily determined by the level of PI3K/Akt/mTOR in tumor cells. We further show that the clinical response of breast cancer patients undergoing neoadjuvant endocrine therapy is associated with the reparative stromal reaction. We conclude that tumor level and localization of pS6 are associated with therapeutic response in breast cancer and represent biomarkers to distinguish which tumors will benefit from the incorporation of PI3K/Akt/mTOR inhibitors with neoadjuvant endocrine therapy.
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