Tissue Stiffness and Hypoxia Modulate the Integrin-Linked Kinase ILK to Control Breast Cancer Stem-like Cells

• Published in: Cancer research (Chicago, Ill.) Ill.), 2016-09, Vol.76 (18), p.5277-5287
• Main Authors: Pang, Mei-Fong, Siedlik, Michael J, Han, Siyang, Stallings-Mann, Melody, Radisky, Derek C, Nelson, Celeste M
• Format: Article
• Language: English
• Subjects: Animals; Breast Neoplasms - enzymology; Breast Neoplasms - pathology; Cell Hypoxia - physiology; Cell Line, Tumor; Female; Flow Cytometry; Humans; Image Processing, Computer-Assisted; Immunoblotting; Mice; Neoplastic Stem Cells - enzymology; Neoplastic Stem Cells - pathology; Protein-Serine-Threonine Kinases - metabolism; Real-Time Polymerase Chain Reaction; Time-Lapse Imaging; Tumor Microenvironment - physiology
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-16-0579

Breast tumors are stiffer and more hypoxic than nonmalignant breast tissue. Here we report that stiff and hypoxic microenvironments promote the development of breast cancer stem-like cells (CSC) through modulation of the integrin-linked kinase ILK. Depleting ILK blocked stiffness and hypoxia-dependent acquisition of CSC marker expression and behavior, whereas ectopic expression of ILK stimulated CSC development under softer or normoxic conditions. Stiff microenvironments also promoted tumor formation and metastasis in ovo, where depleting ILK significantly abrogated the tumorigenic and metastatic potential of invasive breast cancer cells. We further found that the ILK-mediated phenotypes induced by stiff and hypoxic microenvironments are regulated by PI3K/Akt. Analysis of human breast cancer specimens revealed an association between substratum stiffness, ILK, and CSC markers, insofar as ILK and CD44 were expressed in cancer cells located in tumor regions predicted to be stiff. Our results define ILK as a key mechanotransducer in modulating breast CSC development in response to tissue mechanics and oxygen tension. Cancer Res; 76(18); 5277-87. ©2016 AACR.