title: Distinct FAK activities determine progenitor and mammary stem cell characteristics.
abstract: Mammary stem cells (MaSC) and progenitor cells are important for mammary gland development and maintenance and may give rise to mammary cancer stem cells (MaCSC). Yet, there remains limited understanding of how these cells contribute to tumorigenesis. Here, we show that conditional deletion of focal adhesion kinase (FAK) in embryonic mammary epithelial cells (MaEC) decreases luminal progenitors and basal MaSCs, reducing their colony-forming and regenerative potentials in a cell-autonomous manner. Loss of FAK kinase activity in MaECs specifically impaired luminal progenitor proliferation and alveologenesis, whereas a kinase-independent activity of FAK supported ductal invasion and basal MaSC activity. Deficiency in luminal progenitors suppressed tumorigenesis and MaCSC formation in a mouse model of breast cancer. In contrast with the general inhibitory effect of FAK attenuation, inhibitors of FAK kinase preferentially inhibited proliferation and tumorsphere formation of luminal progenitor-like, but not MaSC-like, human breast cancer cells. Our findings establish distinct kinase-dependent and -independent activities of FAK that differentially regulate luminal progenitors and basal MaSCs. We suggest that targeting these distinct functions may tailor therapeutic strategies to address breast cancer heterogeneity more effectively.
authors.affiliation: Divisions of Molecular Medicine and Genetics and Hematology and Oncology, Department of Internal Medicine, Comprehensive Cancer Center, and Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Luo
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Zhao
authors.forename: Song
authors.initials: S
authors.lastname: Chen
authors.forename: Suling
authors.initials: S
authors.lastname: Liu
authors.forename: Max S
authors.initials: MS
authors.lastname: Wicha
authors.forename: Jun-Lin
authors.initials: JL
authors.lastname: Guan
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008321:Mammary Glands, Animal / Q000201:enzymology / Q000473:pathology*; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D051379:Mice; D009154:Mutation / Q000235:genetics; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000201:enzymology / Q000473:pathology*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051416:Focal Adhesion Protein-Tyrosine Kinases