Abstract B27: Tackling mammary tumors by disrupting cancer stem cells via modulation of developmental signaling pathways

The master regulators of embryonic development, Cripto and Notch, play key roles in modulating mammary gland morphogenesis and cell fate specification in the embryo through fetal mammary stem cells and in the adult organism particularly within the adult mammary stem cells, which determine mammary progenitor cell lineages that generate the basal/myoepithelial and luminal compartments of the adult mammary gland. Together with recognized transcription factors and embryonic stem cell markers, these embryonic regulatory molecules can be inappropriately augmented during mammary gland tumorigenesis to support the tumor-initiating cell/cancer stem cell (CSC) compartment, and the effects of their deregulation may contribute for the etiology of breast cancer. To investigate a possible interplay of Cripto and Notch pathways in mammary tumorigenesis and CSCs generation/maintenance, we developed a transgenic mouse model overexpressing Notch and lacking Cripto. We observed considerable tumor suppressor effects when one allele of Cripto was deleted, including significant reduction in the number of mammary hyperplasias, increased tumor latency, and the development of histologically well-differentiated tumors, preserving glandular-like mammary structures. Importantly, this phenotype could be associated with a putative role of Cripto in the specification of CSCs, observed by the lack of luminal progenitor markers, decreased tumor-spheres formation, less colonies in soft-agar, and a significantly reduced capacity to initiate mammary tumors in syngeneic FVB/N mice. Therefore, Cripto proved to contribute to Notch tumorigenesis and maintenance of CSCs, by preventing the differentiation of a parity-induced population of luminal progenitor cells, which is the target for Notch transformation. Searching for specific anti-Cripto-1 therapies that could be further translated to the clinic, we treated Notch-overexpressing/Cripto-wt animals with a synthetic anticancer agent, HKH40A, and observed a significant decrease in tumor formation/growth. The negative modulation of these pathways in the clinic may represent an important tool to prevent the generation and maintenance of CSCs, and preclude the initiation/promotion of breast cancer metastatic spread, resistance to therapy, and cancer recurrence. Citation Format: Maria Cristina Rangel, Ahmed Raafat, Nadia P. Castro, Malgorzata Klauzinska, Teresa Kosakowska-Cholody, Fariba Behbod, Stephen Lockett, Robert Callahan, Roger Chammas, David Salomon. Tackling mammary tumors by disrupting cancer stem cells via modulation of developmental signaling pathways [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; Sao Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr B27.