Mammary epithelial-specific ablation of the focal adhesion kinase suppresses mammary tumorigenesis by affecting mammary cancer stem/progenitor cells.
Focal adhesion kinase (FAK) has been implicated in the development of cancers, including those of the breast. Nevertheless, the molecular and cellular mechanisms by which FAK promotes mammary tumorigenesis in vivo are not well understood. Here, we show that targeted deletion of FAK in mouse mammary epithelium significantly suppresses mammary tumorigenesis in a well-characterized breast cancer model. Ablation of FAK leads to the depletion of a subset of bipotent cells in the tumor that express both luminal marker keratin 8/18 and basal marker keratin 5. Using mammary stem/progenitor markers, including aldehyde dehydrogenase, CD24, CD29, and CD61, we further revealed that ablation of FAK reduced the pool of cancer stem/progenitor cells in primary tumors of FAK-targeted mice and impaired their self-renewal and migration in vitro. Finally, through transplantation in NOD-SCID mice, we found that cancer stem/progenitor cells isolated from FAK-targeted mice have compromised tumorigenicity and impaired maintenance in vivo. Together, these results show a novel function of FAK in maintaining the mammary cancer stem/progenitor cell population and provide a novel mechanism by which FAK may promote breast cancer development and progression.
Luo
Ming
M
Department of Internal Medicine, Division of Molecular Medicine and Genetics, Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Fan
Huaping
H
Nagy
Tamas
T
Wei
Huijun
H
Wang
Chenran
C
Liu
Suling
S
Wicha
Max S
MS
Guan
Jun-Lin
JL
D000444:Aldehyde Dehydrogenase / Q000096:biosynthesis; D000818:Animals; D002465:Cell Movement / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology; D004847:Epithelial Cells / Q000473:pathology; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000172:deficiency*; D008321:Mammary Glands, Animal / Q000201:enzymology / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology* / Q000473:pathology*; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D008822:Mice, Transgenic; D014411:Neoplastic Stem Cells / Q000201:enzymology* / Q000473:pathology*
D000444:Aldehyde Dehydrogenase; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse