title: FGFR2 promotes breast tumorigenicity through maintenance of breast tumor-initiating cells.
abstract: Emerging evidence suggests that some cancers contain a population of stem-like TICs (tumor-initiating cells) and eliminating TICs may offer a new strategy to develop successful anti-cancer therapies. As molecular mechanisms underlying the maintenance of the TIC pool are poorly understood, the development of TIC-specific therapeutics remains a major challenge. We first identified and characterized TICs and non-TICs isolated from a mouse breast cancer model. TICs displayed increased tumorigenic potential, self-renewal, heterogeneous differentiation, and bipotency. Gene expression analysis and immunostaining of TICs and non-TICs revealed that FGFR2 was preferentially expressed in TICs. Loss of FGFR2 impaired self-renewal of TICs, thus resulting in marked decreases in the TIC population and tumorigenic potential. Restoration of FGFR2 rescued the defects in TIC pool maintenance, bipotency, and breast tumor growth driven by FGFR2 knockdown. In addition, pharmacological inhibition of FGFR2 kinase activity led to a decrease in the TIC population which resulted in suppression of breast tumor growth. Moreover, human breast TICs isolated from patient tumor samples were found enriched in a FGFR2+ population that was sufficient to initiate tumor growth. Our data suggest that FGFR2 is essential in sustaining the breast TIC pool through promotion of self-renewal and maintenance of bipotent TICs, and raise the possibility of FGFR2 inhibition as a strategy for anti-cancer therapy by eradicating breast TICs.
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California, United States of America. sungeunk@amgen.com
authors.forename: Sungeun
authors.initials: S
authors.lastname: Kim
authors.forename: Anna
authors.initials: A
authors.lastname: Dubrovska
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Salamone
authors.forename: John R
authors.initials: JR
authors.lastname: Walker
authors.forename: Kathryn B
authors.initials: KB
authors.lastname: Grandinetti
authors.forename: Ghislain M C
authors.initials: GM
authors.lastname: Bonamy
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Orth
authors.forename: Jimmy
authors.initials: J
authors.lastname: Elliott
authors.forename: Diana Graus
authors.initials: DG
authors.lastname: Porta
authors.forename: Carlos
authors.initials: C
authors.lastname: Garcia-Echeverria
authors.forename: Venkateshwar A
authors.initials: VA
authors.lastname: Reddy
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism*; D051927:CD24 Antigen / Q000378:metabolism; D018929:Cell Culture Techniques; D002454:Cell Differentiation; D049109:Cell Proliferation; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D015674:Mammary Neoplasms, Animal / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D008856:Microscopy, Fluorescence; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000276:immunology* / Q000378:metabolism; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D051927:CD24 Antigen; D019012:Integrin beta1; C496353:FGFR2 protein, human; C496354:Fgfr2 protein, mouse; D051497:Receptor, Fibroblast Growth Factor, Type 2