title: PTEN Loss in E-Cadherin-Deficient Mouse Mammary Epithelial Cells Rescues Apoptosis and Results in Development of Classical Invasive Lobular Carcinoma.
abstract: Invasive lobular carcinoma (ILC) is an aggressive breast cancer subtype with poor response to chemotherapy. Besides loss of E-cadherin, a hallmark of ILC, genetic inactivation of PTEN is frequently observed in patients. Through concomitant Cre-mediated inactivation of E-cadherin and PTEN in mammary epithelium, we generated a mouse model of classical ILC (CLC), the main histological ILC subtype. While loss of E-cadherin induced cell dissemination and apoptosis, additional PTEN inactivation promoted cell survival and rapid formation of invasive mammary tumors that recapitulate the histological and molecular features, estrogen receptor (ER) status, growth kinetics, metastatic behavior, and tumor microenvironment of human CLC. Combined inactivation of E-cadherin and PTEN is sufficient to cause CLC development. These CLCs showed significant tumor regression upon BEZ235-mediated inhibition of PI3K signaling. In summary, this mouse model provides important insights into CLC development and suggests inhibition of phosphatidylinositol 3-kinase (PI3K) signaling as a potential therapeutic strategy for targeting CLC.
authors.affiliation: Division of Molecular Pathology, the Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
authors.forename: Mirjam C
authors.initials: MC
authors.lastname: Boelens
authors.affiliation: Division of Molecular Pathology, the Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
authors.forename: Micha
authors.initials: M
authors.lastname: Nethe
authors.affiliation: Division of Molecular Pathology, the Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
authors.forename: Sjoerd
authors.initials: S
authors.lastname: Klarenbeek
authors.affiliation: Division of Molecular Pathology, the Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
authors.forename: Julian R
authors.initials: JR
authors.lastname: de Ruiter
authors.affiliation: Division of Molecular Pathology, the Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
authors.forename: Eva
authors.initials: E
authors.lastname: Schut
authors.affiliation: Division of Molecular Carcinogenesis, the Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
authors.forename: Nicola
authors.initials: N
authors.lastname: Bonzanni
authors.affiliation: Section of Molecular Cytology and Van Leeuwenhoek Centre for Advanced Microscopy, University of Amsterdam, Science Park 904, 1098 XH Amsterdam, the Netherlands.
authors.forename: Amber L
authors.initials: AL
authors.lastname: Zeeman
authors.affiliation: Division of Molecular Pathology, the Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
authors.forename: Ellen
authors.initials: E
authors.lastname: Wientjens
authors.affiliation: Division of Molecular Pathology, the Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
authors.forename: Eline
authors.initials: E
authors.lastname: van der Burg
authors.affiliation: Division of Molecular Carcinogenesis, the Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
authors.forename: Lodewyk
authors.initials: L
authors.lastname: Wessels
authors.affiliation: Section of Molecular Cytology and Van Leeuwenhoek Centre for Advanced Microscopy, University of Amsterdam, Science Park 904, 1098 XH Amsterdam, the Netherlands.
authors.forename: Renée
authors.initials: R
authors.lastname: van Amerongen
authors.affiliation: Division of Molecular Pathology, the Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands; Cancer Genomics Netherlands, 3584 CG Utrecht, the Netherlands. Electronic address: j.jonkers@nki.nl.
authors.forename: Jos
authors.initials: J
authors.lastname: Jonkers
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D015820:Cadherins / Q000172:deficiency / Q000235:genetics*; D018275:Carcinoma, Lobular / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D007093:Imidazoles / Q000494:pharmacology; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009361:Neoplasm Invasiveness; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016019:Survival Analysis; D059016:Tumor Microenvironment
chemical_list: D000970:Antineoplastic Agents; D015820:Cadherins; D007093:Imidazoles; D019426:Integrases; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines; D011960:Receptors, Estrogen; C000611838:Cdh1 protein, mouse; C045073:Cre recombinase; C487757:Pten protein, mouse; C531198:dactolisib
keywords: BEZ235; Cre-lox; E-cadherin; PTEN; breast cancer; classical invasive lobular carcinoma; genetically engineered mouse model; metastasis; tumor microenvironment