期刊
CELL REPORTS
卷 16, 期 8, 页码 2087-2101出版社
CELL PRESS
DOI: 10.1016/j.celrep.2016.07.059
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资金
- Dutch Cancer Society [NKI 2015-7589]
- Netherlands Organization for Scientific Research [VENI 016156012, NGI-Zenith 93512009, VICI 91814643]
- Cancer Genomics Netherlands [CGCNL]
- Cancer Systems Biology Center [CSBC]
- National Roadmap grant for the Mouse Clinic for Cancer and Aging research [MCCA])
- European Union Seventh Framework Programme [260791, 312325]
- European Research Council (ERC Synergy project CombatCancer)
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.
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