High collagen density augments mTOR-dependent cancer stem cells in ERα+ mammary carcinomas, and increases mTOR-independent lung metastases. (1st October 2018)

• Record Type: Journal Article
• Authors: Shea, Michael P.; O'Leary, Kathleen A.; Wegner, Kyle A.; Vezina, Chad M.; Schuler, Linda A.
• Is Part Of: Cancer letters. Volume 433(2018)
• Page Start: 1
• Page End: 9
• Publication Date: 2018-10-01
• Subjects: Breast cancer -- Luminal B subtype -- Extracellular matrix density/ stiffness -- Cancer stem cells -- mTOR; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2018.06.025
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: Metastatic estrogen receptor alpha positive (ERα+) cancers account for most breast cancer mortality. Cancer stem cells (CSCs) and dense/stiff extracellular matrices are implicated in aggression and therapy resistance. We examined this interplay and response to mTOR inhibition using ERα+ adenocarcinomas from NRL-PRL females in combination with Col1a1 tmJae/+ (mCol1a1) mice, which accumulate collagen-I around growing tumors. Orthotopic transplantation of tumor cells to mCol1a1 but not wildtype hosts resulted in striking desmoplasia. Mammary tumors in mCol1a1 recipients displayed higher CSC activity and enhanced AKT-mTOR and YAP activation, and these animals developed more and larger lung metastases. Treatment with the mTOR inhibitor, rapamycin, with or without the anti-estrogen, ICI182780, rapidly diminished mammary tumors, which rapidly reversed when treatment ceased. In contrast, lung metastases, which exhibited lower proliferation and pS6RP, indicating lower mTOR activity, were unresponsive, and mCol1a1 hosts continued to sustain greater metastatic burdens. These findings shed light on the influence of desmoplastic tumor microenvironments on the CSC niche and metastatic behavior in ERα+ breast cancer. The differential mTOR dependence of local mammary tumors and pulmonary lesions has implications for success of mTOR inhibitors in advanced ERα+ disease. Highlights: Dense/stiff microenvironments enhanced CSC activity, AKT-mTOR and YAP activation. Inhibition of mTOR ± ICI182780 rapidly but not durably diminished mammary tumors. Lung metastases, which exhibited lower mTOR activity, were unresponsive. mCol1a1 hosts continued to sustain greater metastatic burdens despite treatment.