title: FER kinase promotes breast cancer metastasis by regulating α6- and β1-integrin-dependent cell adhesion and anoikis resistance.
abstract: Metastatic breast cancer cannot be treated successfully. Currently, the targeted therapies for metastatic disease are limited to human epidermal growth factor receptor 2 and hormone receptor antagonists. Understanding the mechanisms of breast cancer growth and metastasis is therefore crucial for the development of new intervention strategies. Here, we show that FER kinase (FER) controls migration and metastasis of invasive human breast cancer cell lines by regulating α6- and β1-integrin-dependent adhesion. Conversely, the overexpression of FER in non-metastatic breast cancer cells induces pro-invasive features. FER drives anoikis resistance, regulates tumour growth and is necessary for metastasis in a mouse model of human breast cancer. In human invasive breast cancer, high FER expression is an independent prognostic factor that correlates with high-grade basal/triple-negative tumours and worse overall survival, especially in lymph node-negative patients. These findings establish FER as a promising target for the prevention and inhibition of metastatic breast cancer.
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: I A
authors.initials: IA
authors.lastname: Ivanova
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: J F
authors.initials: JF
authors.lastname: Vermeulen
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: C
authors.initials: C
authors.lastname: Ercan
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: J M
authors.initials: JM
authors.lastname: Houthuijzen
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: F A
authors.initials: FA
authors.lastname: Saig
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: E J
authors.initials: EJ
authors.lastname: Vlug
authors.affiliation: 1] Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands [2] Division of Internal Medicine and Dermatology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: van der Wall
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: P J
authors.initials: PJ
authors.lastname: van Diest
authors.affiliation: 1] Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands [2] Department of Radiation Oncology, Maastricht University Medical Center+, Maastricht, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Vooijs
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: P W B
authors.initials: PW
authors.lastname: Derksen
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D023102:Anoikis / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D002448:Cell Adhesion / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D004195:Disease Models, Animal; D018450:Disease Progression; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D006801:Humans; D039503:Integrin alpha6 / Q000378:metabolism*; D019012:Integrin beta1 / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009362:Neoplasm Metastasis; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D047368:Tumor Burden
chemical_list: D000199:Actins; D039503:Integrin alpha6; D019012:Integrin beta1; C052602:proto-oncogene protein c-fes-fps; D011505:Protein-Tyrosine Kinases