title: Loss of p120-catenin induces metastatic progression of breast cancer by inducing anoikis resistance and augmenting growth factor receptor signaling.
abstract: Metastatic breast cancer remains the chief cause of cancer-related death among women in the Western world. Although loss of cell-cell adhesion is key to breast cancer progression, little is known about the underlying mechanisms that drive tumor invasion and metastasis. Here, we show that somatic loss of p120-catenin (p120) in a conditional mouse model of noninvasive mammary carcinoma results in formation of stromal-dense tumors that resemble human metaplastic breast cancer and metastasize to lungs and lymph nodes. Loss of p120 in anchorage-dependent breast cancer cell lines strongly promoted anoikis resistance through hypersensitization of growth factor receptor (GFR) signaling. Interestingly, p120 deletion also induced secretion of inflammatory cytokines, a feature that likely underlies the formation of the prometastatic microenvironment in p120-negative mammary carcinomas. Our results establish a preclinical platform to develop tailored intervention regimens that target GFR signals to treat p120-negative metastatic breast cancers.
authors.affiliation: Department of Pathology, Cancer Center, and Division of Internal Medicine, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Ron C J
authors.initials: RC
authors.lastname: Schackmann
authors.forename: Sjoerd
authors.initials: S
authors.lastname: Klarenbeek
authors.forename: Eva J
authors.initials: EJ
authors.lastname: Vlug
authors.forename: Suzan
authors.initials: S
authors.lastname: Stelloo
authors.forename: Miranda
authors.initials: M
authors.lastname: van Amersfoort
authors.forename: Milou
authors.initials: M
authors.lastname: Tenhagen
authors.forename: Tanya M
authors.initials: TM
authors.lastname: Braumuller
authors.forename: Jeroen F
authors.initials: JF
authors.lastname: Vermeulen
authors.forename: Petra
authors.initials: P
authors.lastname: van der Groep
authors.forename: Ton
authors.initials: T
authors.lastname: Peeters
authors.forename: Elsken
authors.initials: E
authors.lastname: van der Wall
authors.forename: Paul J
authors.initials: PJ
authors.lastname: van Diest
authors.forename: Jos
authors.initials: J
authors.lastname: Jonkers
authors.forename: Patrick W B
authors.initials: PW
authors.lastname: Derksen
mesh_terms: D000818:Animals; D023102:Anoikis / Q000502:physiology*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D051177:Catenins / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D009361:Neoplasm Invasiveness / Q000473:pathology; D017978:Receptors, Growth Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D000095002:Delta Catenin
chemical_list: D051177:Catenins; D017978:Receptors, Growth Factor; D000095002:Delta Catenin