Notch as master regulator of breast cancer subtype and intratumoural heterogeneity

Tumour heterogeneity is a driving force for disease progression and one of the major obstacles to effective treatment. Heterogeneity is driven by mutations and other processes that generate diverse cancer cell phenotypes and functions. Uncovering the pathways controlling this diversity is of critical importance for the development of effective therapies targeting distinct cell types, and, potentially, for inducing changes in tumour differentiation status.

Estrogen receptor-negative breast tumours include cells with a mixture of differentiated states. Cellular heterogeneity within these cancers can lead to the generation of subpopulations that resist therapy. In many biological systems, signaling through so-called “Notch” receptors is used to create the cell diversity associated with functional tissues. This issue represents a challenge with respect to the development of effective treatment for breast cancer.

This project aims to define mechanisms by which breast cancer cellular diversity or heterogeneity develops and is maintained. Since Notch signaling is activated in so many types of breast cancers and leads to regulation of cell fate in this context, results from this project may help to identify how these receptors can be targeted for therapeutic benefit.

The project is being implemented by the Hospital for Sick Children in Toronto, the Hebrew University of Jerusalem (Israel), and the Indian Institute of Science. It was selected for funding through the third research competition of the Joint Canada-Israel Health Research Program, a partnership between IDRC, the Canadian Institutes of Health Research, the Israel Science Foundation, and the Azrieli Foundation.