Breast cancer, the most frequent tumor type in women, is a heterogeneous disease classified into different histological and molecular subtypes presenting distinct outcomes. In addition to this inter-tumor heterogeneity, breast tumors exhibit intra-tumor heterogeneity. In Clinics, tumor heterogeneity is hold responsible for disease progression and therapy failure. The current key question in breast cancer biology is therefore to elucidate origins of breast cancer heterogeneity. The cell-of-origin concept has been proposed to explain inter-tumor heterogeneity: the first transformed cell defines the tumor type. The contribution of mammary stem cells (MSCs) to tumorigenesis and their clinical implications are still unknown and poorly investigated. A population of MSCs was recently identified on the basis of expression of the Protein C Receptor (Procr) in humans and mice. By using transgenic mouse models, we conditionally introduced mutations and a fluorescent reporter within Procr+ MSCs.
The main objectives were to:
1. Decipher the fate of MSCs (Procr+ cells) upon oncogenic perturbations (lineage tracing) and define their molecular characteristics;
2. Analyze the mammary tumors evoked by different mutations in Procr+ MSCs, and to assess the stem-like properties and metastatic potential of Procr+ cancer cells;
At the end of the funding, we have achieved our main objectives by showing that:
• Procr+ MSCs are cells of origin of mammary tumors
• Mutant-Procr+ MSCs give rise to poorly differentiated tumors enriched in mesenchymal and stem cells features
• Mutant-Procr+ MSCs have Cancer Stem Cells properties
