title: Activation of PI3K/Akt/mTOR signaling in the tumor stroma drives endocrine therapy-dependent breast tumor regression.
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.
authors.affiliation: Instituto de Biología y Medicina Experimental, Protein Kinases and Cancer Laboratory, Buenos Aires, Argentina.
authors.forename: María Laura
authors.initials: ML
authors.lastname: Polo
authors.affiliation: Instituto de Biología y Medicina Experimental, Protein Kinases and Cancer Laboratory, Buenos Aires, Argentina.
authors.forename: Marina
authors.initials: M
authors.lastname: Riggio
authors.affiliation: Instituto de Biología y Medicina Experimental, Protein Kinases and Cancer Laboratory, Buenos Aires, Argentina.
authors.forename: María
authors.initials: M
authors.lastname: May
authors.affiliation: Instituto de Biología y Medicina Experimental, Protein Kinases and Cancer Laboratory, Buenos Aires, Argentina.
authors.forename: María Jimena
authors.initials: MJ
authors.lastname: Rodríguez
authors.affiliation: Instituto de Biología y Medicina Experimental, Protein Kinases and Cancer Laboratory, Buenos Aires, Argentina.
authors.forename: María Cecilia
authors.initials: MC
authors.lastname: Perrone
authors.affiliation: Mayo Clinic Comprehensive Cancer Center, Department of Cancer Biology, Jacksonville, FL, USA.
authors.forename: Melody
authors.initials: M
authors.lastname: Stallings-Mann
authors.affiliation: Centro Oncológico Riojano Integral, Medical Oncology, La Rioja, Argentina.
authors.forename: Diego
authors.initials: D
authors.lastname: Kaen
authors.affiliation: Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Marlene
authors.initials: M
authors.lastname: Frost
authors.affiliation: Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Goetz
authors.affiliation: Department of Surgery, Mayo Clinic, Rochester, MN, USA.
authors.forename: Judy
authors.initials: J
authors.lastname: Boughey
authors.affiliation: Instituto de Biología y Medicina Experimental, Protein Kinases and Cancer Laboratory, Buenos Aires, Argentina.
authors.forename: Claudia
authors.initials: C
authors.lastname: Lanari
authors.affiliation: Mayo Clinic Comprehensive Cancer Center, Department of Cancer Biology, Jacksonville, FL, USA.
authors.forename: Derek
authors.initials: D
authors.lastname: Radisky
authors.affiliation: Instituto de Biología y Medicina Experimental, Protein Kinases and Cancer Laboratory, Buenos Aires, Argentina.
authors.forename: Virginia
authors.initials: V
authors.lastname: Novaro
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D020847:Estrogen Receptor Modulators / Q000494:pharmacology; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D017154:Stromal Cells / Q000201:enzymology / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D000077191:Wortmannin; D023041:Xenograft Model Antitumor Assays
chemical_list: D000730:Androstadienes; D020847:Estrogen Receptor Modulators; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D000077191:Wortmannin; C546842:MTOR protein, human
keywords: PI3K/Akt pathway; breast cancer; neoadjuvant endocrine therapy; tumor stroma