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

• Published in: Oncotarget Vol. 6; no. 26; pp. 22081 - 22097
• Main Authors: Polo, María Laura, Riggio, Marina, May, María, Rodríguez, María Jimena, Perrone, María Cecilia, Stallings-Mann, Melody, Kaen, Diego, Frost, Marlene, Goetz, Matthew, Boughey, Judy, Lanari, Claudia, Radisky, Derek, Novaro, Virginia
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 08.09.2015
• Subjects: Aged; Aged, 80 and over; Androstadienes - pharmacology; Animals; Breast Neoplasms - drug therapy; Breast Neoplasms - enzymology; Breast Neoplasms - pathology; Carcinoma, Ductal, Breast - drug therapy; Carcinoma, Ductal, Breast - enzymology; Carcinoma, Ductal, Breast - pathology; Estrogen Receptor Modulators - pharmacology; Female; Humans; Mammary Neoplasms, Experimental - drug therapy; Mammary Neoplasms, Experimental - enzymology; Mammary Neoplasms, Experimental - pathology; Mice; Mice, Inbred BALB C; Middle Aged; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphatidylinositol 3-Kinases - metabolism; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - metabolism; Research Paper; Signal Transduction; Stromal Cells - enzymology; Stromal Cells - pathology; TOR Serine-Threonine Kinases - metabolism; Xenograft Model Antitumor Assays; breast cancer; PI3K/Akt pathway; neoadjuvant endocrine therapy; tumor stroma
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.4203

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.