p120-Catenin Is Critical for the Development of Invasive Lobular Carcinoma in Mice

Tenhagen, Milou; Klarenbeek, Sjoerd; Braumuller, Tanya M.; Hofmann, Ilse; Groep, Petra van der; Hoeve, Natalie ter; Wall, Elsken van der; Jonkers, Jos; Derksen, Patrick W.B.

doi:10.1007/s10911-016-9358-3

Cited by 12 publications

(9 citation statements)

References 34 publications

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“…Inactivation of the AJ as a whole is not the determining factor for the formation of lobular breast cancer. Whereas somatic ablation of E‐cadherin in the mammary gland results in metastatic mouse ILC , inactivation of the AJ through p120 loss induces the formation of invasive high‐grade and basal‐like IDC . It appears that ILC may uniquely depend on Rho/Rock‐driven actin remodeling, given that p120 null mammary carcinoma cells and IDC‐derived human tumor cell lines (e.g.…”

Section: Discussionmentioning

confidence: 99%

αE‐catenin is a candidate tumor suppressor for the development of E‐cadherin‐expressing lobular‐type breast cancer

Groot

Rätze

Amersfoort

et al. 2018

The Journal of Pathology

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Although mutational inactivation of E‐cadherin (CDH1) is the main driver of invasive lobular breast cancer (ILC), approximately 10–15% of all ILCs retain membrane‐localized E‐cadherin despite the presence of an apparent non‐cohesive and invasive lobular growth pattern. Given that ILC is dependent on constitutive actomyosin contraction for tumor development and progression, we used a combination of cell systems and in vivo experiments to investigate the consequences of α‐catenin (CTNNA1) loss in the regulation of anchorage independence of non‐invasive breast carcinoma. We found that inactivating somatic CTNNA1 mutations in human breast cancer correlated with lobular and mixed ducto‐lobular phenotypes. Further, inducible loss of α‐catenin in mouse and human E‐cadherin‐expressing breast cancer cells led to atypical localization of E‐cadherin, a rounded cell morphology, and anoikis resistance. Pharmacological inhibition experiments subsequently revealed that, similar to E‐cadherin‐mutant ILC, anoikis resistance induced by α‐catenin loss was dependent on Rho/Rock‐dependent actomyosin contractility. Finally, using a transplantation‐based conditional mouse model, we demonstrate that inducible inactivation of α‐catenin instigates acquisition of lobular features and invasive behavior. We therefore suggest that α‐catenin represents a bona fide tumor suppressor for the development of lobular‐type breast cancer and as such provides an alternative event to E‐cadherin inactivation, adherens junction (AJ) dysfunction, and subsequent constitutive actomyosin contraction. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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Section: Discussionmentioning

confidence: 99%

αE‐catenin is a candidate tumor suppressor for the development of E‐cadherin‐expressing lobular‐type breast cancer

Groot

Rätze

Amersfoort

et al. 2018

The Journal of Pathology

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“…Elegant genetically engineered mouse models carrying various mutations in conjunction with CDH1 deletion, mimic different aspects of the disease (Derksen et al , 2006; Boelens et al , 2016; Tenhagen et al , 2016; An et al , 2018) and of particular subtypes, such as the classic (Boelens et al , 2016) or inflammatory ILC (An et al , 2018). However, these models lack the high ER and PR expression characteristic of the human disease and are of limited value in mimicking the metastatic disease.…”

Section: Introductionmentioning

confidence: 99%

Intraductal xenografts show lobular carcinoma cells rely on their own extracellular matrix and LOXL1

et al. 2021

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Invasive lobular carcinoma (ILC) is the most frequent special histological subtype of breast cancer, typically characterized by loss of E‐cadherin. It has clinical features distinct from other estrogen receptor‐positive (ER+) breast cancers but the molecular mechanisms underlying its characteristic biology are poorly understood because we lack experimental models to study them. Here, we recapitulate the human disease, including its metastatic pattern, by grafting ILC‐derived breast cancer cell lines, SUM‐44 PE and MDA‐MB‐134‐VI cells, into the mouse milk ducts. Using patient‐derived intraductal xenografts from lobular and non‐lobular ER+ HER2− tumors to compare global gene expression, we identify extracellular matrix modulation as a lobular carcinoma cell‐intrinsic trait. Analysis of TCGA patient datasets shows matrisome signature is enriched in lobular carcinomas with overexpression of elastin, collagens, and the collagen modifying enzyme LOXL1. Treatment with the pan LOX inhibitor BAPN and silencing of LOXL1 expression decrease tumor growth, invasion, and metastasis by disrupting ECM structure resulting in decreased ER signaling. We conclude that LOXL1 inhibition is a promising therapeutic strategy for ILC.

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“…However, when inactivated in conjunction with p53, loss of p120 did not result in tumors with an ILC-like morphology [132]. Moreover, deletion of p120 catenin in addition to E-cadherin and p53 did not accelerate tumor formation, and the morphology of these triple-knockout tumors was predominantly sarcomatoid [133]. This indicated that cytoplasmic p120 catenin is required for the development of ILC in mice.…”

Section: Genetically Engineered Ilc Mouse Modelsmentioning

confidence: 95%

Atlas of Lobular Breast Cancer Models: Challenges and Strategic Directions

Sflomos

Schipper

Koorman

et al. 2021

Cancers

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Invasive lobular carcinoma (ILC) accounts for up to 15% of all breast cancer (BC) cases and responds well to endocrine treatment when estrogen receptor α-positive (ER+) yet differs in many biological aspects from other ER+ BC subtypes. Up to 30% of patients with ILC will develop late-onset metastatic disease up to ten years after initial tumor diagnosis and may experience failure of systemic therapy. Unfortunately, preclinical models to study ILC progression and predict the efficacy of novel therapeutics are scarce. Here, we review the current advances in ILC modeling, including cell lines and organotypic models, genetically engineered mouse models, and patient-derived xenografts. We also underscore four critical challenges that can be addressed using ILC models: drug resistance, lobular tumor microenvironment, tumor dormancy, and metastasis. Finally, we highlight the advantages of shared experimental ILC resources and provide essential considerations from the perspective of the European Lobular Breast Cancer Consortium (ELBCC), which is devoted to better understanding and translating the molecular cues that underpin ILC to clinical diagnosis and intervention. This review will guide investigators who are considering the implementation of ILC models in their research programs.

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p120-Catenin Is Critical for the Development of Invasive Lobular Carcinoma in Mice

Cited by 12 publications

References 34 publications

αE‐catenin is a candidate tumor suppressor for the development of E‐cadherin‐expressing lobular‐type breast cancer

αE‐catenin is a candidate tumor suppressor for the development of E‐cadherin‐expressing lobular‐type breast cancer

Intraductal xenografts show lobular carcinoma cells rely on their own extracellular matrix and LOXL1

Atlas of Lobular Breast Cancer Models: Challenges and Strategic Directions

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