title: p120-Catenin Is Critical for the Development of Invasive Lobular Carcinoma in Mice.
abstract: Loss of E-cadherin expression is causal to the development of invasive lobular breast carcinoma (ILC). E-cadherin loss leads to dismantling of the adherens junction and subsequent translocation of p120-catenin (p120) to the cytosol and nucleus. Although p120 is critical for the metastatic potential of ILC through the regulation of Rock-dependent anoikis resistance, it remains unknown whether p120 also contributes to ILC development. Using genetically engineered mouse models with mammary gland-specific inactivation of E-cadherin, p120 and p53, we demonstrate that ILC formation induced by E-cadherin and p53 loss is severely impaired upon concomitant inactivation of p120. Tumors that developed in the triple-knockout mice were mostly basal sarcomatoid carcinomas that displayed overt nuclear atypia and multinucleation. In line with the strong reduction in ILC incidence in triple-knockout mice compared to E-cadherin and p53 double-knockout mice, no functional redundancy of p120 family members was observed in mouse ILC development, as expression and localization of ARVCF, p0071 or δ-catenin was unaltered in ILCs from triple-knockout mice. In conclusion, we show that loss of p120 in the context of the p53-deficient mouse models is dominant over E-cadherin inactivation and its inactivation promotes the development of basal, epithelial-to-mesenchymal-transition (EMT)-type invasive mammary tumors.
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Milou
authors.initials: M
authors.lastname: Tenhagen
authors.affiliation: Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Sjoerd
authors.initials: S
authors.lastname: Klarenbeek
authors.affiliation: Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Tanya M
authors.initials: TM
authors.lastname: Braumuller
authors.affiliation: Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Vascular Biology and Tumor Angiogenesis, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.
authors.forename: Ilse
authors.initials: I
authors.lastname: Hofmann
authors.affiliation: Department of Medical Oncology, Cancer Center, UMC Utrecht, Utrecht, The Netherlands.
authors.forename: Petra
authors.initials: P
authors.lastname: van der Groep
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Natalie
authors.initials: N
authors.lastname: Ter Hoeve
authors.affiliation: Department of Medical Oncology, Cancer Center, UMC Utrecht, Utrecht, The Netherlands.
authors.forename: Elsken
authors.initials: E
authors.lastname: van der Wall
authors.affiliation: Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Jos
authors.initials: J
authors.lastname: Jonkers
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands. pderksen@umcutrecht.nl.
authors.forename: Patrick W B
authors.initials: PW
authors.lastname: Derksen
mesh_terms: D000818:Animals; D015820:Cadherins / Q000378:metabolism*; D018275:Carcinoma, Lobular / Q000378:metabolism* / Q000473:pathology*; D051177:Catenins / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D009361:Neoplasm Invasiveness; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D000095002:Delta Catenin
chemical_list: D015820:Cadherins; D051177:Catenins; D016159:Tumor Suppressor Protein p53; D000095002:Delta Catenin; C000722349:Ctnnd1 protein, mouse
keywords: Breast cancer; Invasive lobular carcinoma; Mouse model; p120