Mammary-specific inactivation of E-cadherin and p53 impairs functional gland development and leads to pleomorphic invasive lobular carcinoma in mice

Patrick W B Derksen,Marten Hornsveld,Eline Van Der Burg,Elly Mesman,Tanya M Braumuller,Jos Jonkers,Jelle Wesseling,Paul Krimpenfort

doi:10.1242/dmm.006395

Abstract

SUMMARYBreast cancer is the most common malignancy in women of the Western world. Even though a large percentage of breast cancer patients show pathological complete remission after standard treatment regimes, approximately 30–40% are non-responsive and ultimately develop metastatic disease. To generate a good preclinical model of invasive breast cancer, we have taken a tissue-specific approach to somatically inactivate p53 and E-cadherin, the cardinal cell-cell adhesion receptor that is strongly associated with tumor invasiveness. In breast cancer, E-cadherin is found mutated or otherwise functionally silenced in invasive lobular carcinoma (ILC), which accounts for 10–15% of all breast cancers. We show that mammary-specific stochastic inactivation of conditional E-cadherin and p53 results in impaired mammary gland function during pregnancy through the induction of anoikis resistance of mammary epithelium, resulting in loss of epithelial organization and a dysfunctional mammary gland. Moreover, combined inactivation of E-cadherin and p53 induced lactation-independent development of invasive and metastatic mammary carcinomas, which showed strong resemblance to human pleomorphic ILC. Dissemination patterns of mouse ILC mimic the human malignancy, showing metastasis to the gastrointestinal tract, peritoneum, lung, lymph nodes and bone. Our results confirm that loss of E-cadherin contributes to both mammary tumor initiation and metastasis, and establish a preclinical mouse model of human ILC that can be used for the development of novel intervention strategies to treat invasive breast cancer.

Highlights

Breast cancer affects a large number of females in the Western world, accounting for half a million deaths worldwide on an annual basis
Carcinoma of the breast is a heterogeneous disease based on pathological criteria, which is probably due to the multiplicity of genetic lesions that have accumulated during tumor development, resulting in distinct tumor types
We have previously shown that somatic inactivation of E-cadherin and p53 in K14-expressing cells induces the formation of mouse ILC (mILC) (Derksen et al, 2006)

Summary

Introduction

Breast cancer affects a large number of females in the Western world, accounting for half a million deaths worldwide on an annual basis. Carcinoma of the breast is a heterogeneous disease based on pathological criteria, which is probably due to the multiplicity of genetic lesions that have accumulated during tumor development, resulting in distinct tumor types. The most frequently observed subtypes, invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC), are very distinct phenotypically as well as biochemically (Coradini et al, 2002; Korkola et al, 2003; Mathieu et al, 2004; Zhao et al, 2004; Stange et al, 2006). ILC is a subtype of breast cancer that accounts for 10-15% of all cases and has a Received 23 July 2010; Accepted 16 December 2010. Loss of E-cadherin, which we have postulated as the initiating and causal event in the development of mouse ILC (mILC) (Derksen et al, 2006), is a common feature of LCIS as well of the adjacent ILC cells (Vos et al, 1997)

Methods

Results

Discussion

Conclusion