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

María Laura Polo, Marina Riggio, María May, María Jimena Rodríguez, María Cecilia Perrone, Melody Stallings-Mann, Diego Kaen, Marlene Frost, Matthew Goetz, Judy Boughey, Claudia Lanari, Derek Radisky, Virginia Novaro

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)22081-22097
Number of pages17
JournalOncotarget
Volume6
Issue number26
DOIs
StatePublished - 2015

Keywords

  • Breast cancer
  • Neoadjuvant endocrine therapy
  • PI3K/Akt pathway
  • Tumor stroma

ASJC Scopus subject areas

  • Oncology

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    Polo, M. L., Riggio, M., May, M., Rodríguez, M. J., Perrone, M. C., Stallings-Mann, M., Kaen, D., Frost, M., Goetz, M., Boughey, J., Lanari, C., Radisky, D., & Novaro, V. (2015). Activation of PI3K/Akt/mTOR signaling in the tumor stroma drives endocrine therapy-dependent breast tumor regression. Oncotarget, 6(26), 22081-22097. https://doi.org/10.18632/oncotarget.4203