Molecular determinants of mammary differentiation and breast cancer progression

Abstract

The mammary epithelium is an architecturally complex tissue comprising of multiple cell lineages. Development and maintenance of this tissue are carefully orchestrated by balancing stem and progenitor cell self-renewal and differentiation. The mammary epithelium must also endure the successive regenerative cycles of pregnancy and lactation. Therefore, it is not surprising that the fidelity of these processes is of the utmost importance to ensure proper homeostasis of this tissue. In fact, dysregulation of these processes frequently results in progression toward cancer, and later, potentially metastatic disease. The clinical relevance of metastasis is hard to overstate, as it is responsible for over 90% of cancer-related deaths. In this thesis, I have identified a number of determinants involved in breast cancer progression and mammary differentiation. First, I describe SMARCE, a SWI-SNF component, as a prognostic factor of carcinoma progression. We show that SMARCE1 cooperates with ILF3 to regulate a basement membrane module and that it is functionally required to degrade basement membrane. Afterwards, I describe CREB3L1 as a key mediator of PERK-driven metastasis. We also showed that the unique mode of action of CREB3L1 provides a therapeutic opportunity to drug invasive breast cancers. Finally, I describe a 3D differentiation screen which identified the collagen receptor tyrosine kinase, DDR1, as a regulator of mammary stem cell differentiation. Mechanistically, we coupled ex vivo functional assays with single cell transcriptomic sequencing to show that DDR1 is required for basal fate commitment to activate JAG1 expression, which indirectly stimulates luminal NOTCH1 signaling to drive lobulogenesis. Collectively, these data provide insight into key molecular regulators of breast cancer progression and mammary differentiation.