Breast cancer is the most common malignancy among females in the Western world, affecting 12% of the global female population and resulting in approximately half a million deaths annually. In breast cancer, loss of E-cadherin is a decisive marker in the differential diagnosis of lobular and ductal carcinoma. While lobular carcinomas show loss of E-cadherin, most other breast carcinomas have retained expression. E-cadherin is a key component of adherens junctions, structures that play crucial roles in the maintenance of tissue integrity. Dysfunction of epithelial adhesion complexes is strongly related to breast cancer invasion and metastasis, the major cause of death in breast cancer patients.
We are using mouse models of breast cancer in which inactivation of E-cadherin induces the formation of mouse invasive lobular carcinoma (mILC), reminiscent of the human condition. Human invasive lobular carcinoma (ILC) is the second most common breast malignancy, with a greater tendency to be multifocal, bilateral and invasive than other types of breast cancer. Metastatic ILC shows overall unresponsiveness to standard treatment regimes, urging the need for alternative intervention strategies.
The mILC models show that disruption of the cadherin/catenin complex confers cell survival at distant organs, increases cell motility, invasiveness and facilitates tumor-related blood vessel formation, processes that propel metastatic spread. We are aiming at combining expertise on adhesion molecules, cell signaling and state-of-the-art mouse models. We are employing several cell lines from our mouse models and human breast cancer that provide a solid cell biological basis for achieving these goals.
We hope to identify the molecular signals that are initiated upon loss of E-cadherin, which will enable our understanding of breast cancer development and progression. For validation purposes, we have developed robust in vivo tumor progression and metastasis assays, based on orthotopic transplantation and bioluminescence imaging of luciferase-expressing cell lines, tumors and primary conditional and wild-type mouse mammary epithelial cells. We will use these assays to validate genes that are nominated as novel regulators of tumor initiation and progression.
