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Cell Rep. 2016 Aug 23;16(8):2087-2101. doi: 10.1016/j.celrep.2016.07.059. Epub 2016 Aug 11.

PTEN Loss in E-Cadherin-Deficient Mouse Mammary Epithelial Cells Rescues Apoptosis and Results in Development of Classical Invasive Lobular Carcinoma.

Author information

1
Division of Molecular Pathology, the Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
2
Division of Molecular Carcinogenesis, the Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
3
Section of Molecular Cytology and Van Leeuwenhoek Centre for Advanced Microscopy, University of Amsterdam, Science Park 904, 1098 XH Amsterdam, the Netherlands.
4
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.

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.

KEYWORDS:

BEZ235; Cre-lox; E-cadherin; PTEN; breast cancer; classical invasive lobular carcinoma; genetically engineered mouse model; metastasis; tumor microenvironment

PMID:
27524621
PMCID:
PMC4999419
DOI:
10.1016/j.celrep.2016.07.059
[Indexed for MEDLINE]
Free PMC Article

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