Abstract IA10: Using lineage tracing and clonal analysis to unravel mammary gland expansion and cancer initiation

Abstract

Abstract We developed novel lineage tracing approaches in mice to decipher the cellular hierarchy of the mammary epithelium during development, adulthood, pregnancy and lactation and to study the cell of origin of different types of breast cancers. Knowing that luminal cells specifically express the keratins K8 and K18, while myoepithelial cells express K5 an K14, we generated two inducible CRE recombinase (CREER) mice expressed in the luminal cells, under the control of K8 and K18 promoters to target luminal cells. To target myoepithelial cells, we used mice expressing the CREER under the control of K5 promoter, as well as the K14rtTA-TetOCRE mice. We demonstrated that the mammary gland initially develops from multipotent embryonic progenitors expressing K14, which give rise upon differentiation to both myoepithelial and luminal cells. However, during puberty and homeostasis, as well as during pregnancy and lactation, the expansion and the maintenance of luminal cells is ensured by the presence of luminal unipotent SCs, while the expansion and maintenance of myoepithelial cells is ensured by the presence of myoepithelial unipotent SCs, rather than being maintained by rare multipotent SCs. We also demonstrated that transplantation assays, while extremely informative about the differentiation potential of tissue specific SCs, can be misleading in extrapolating the differentiation potential of SCs under physiological conditions. While the different genes implicated in inherited and sporadic breast cancers have been identified, the cellular origin of the different types of breast cancers remains elusive. Mutations in the cancer suppressor genes BRCA (BRCA1 and BRCA2) account for the majority of inherited breast cancers, and are associated with basal-like tumors. Oncogenic mutations in PIK3CA are found in 20 to 40% of invasive breast cancers and are associated with luminal tumors. To determine the cell of origin of breast cancers, we use the K8CREER mice to introduce oncogenic mutations specifically in luminal cells, while we use the K5CREER mice to introduce the mutations in basal cells. We target deletion of Brca1 and p53 to recapitulate basal-like breast cancers, while expression of the oncogene PIK3CA is used to recapitulate luminal-like breast cancers. Our results show that the differentiation of breast tumors can be misleading to extrapolate their cellular origin and that cell fate changes occur during breast cancer initiation. Citation Format: Alexandra Van Keymeulen, May Yin Lee, Marielle Ousset, Cédric Blanpain. Using lineage tracing and clonal analysis to unravel mammary gland expansion and cancer initiation. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr IA10.