Targenting stemness as a strategy for treating triple-negative breast cancer

• Grant number: 18/08107-2
• Support Opportunities: Research Grants - Young Investigators Grants
• Start date: April 01, 2019
• End date: March 31, 2023
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: Maria Cristina Rodrigues Rangel
• Grantee: Maria Cristina Rodrigues Rangel
• Host Institution: Instituto do Câncer do Estado de São Paulo Octavio Frias de Oliveira (ICESP). Coordenadoria de Serviços de Saúde (CSS). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
• Associated researchers: Roger Chammas
• Associated research grant(s): 20/15445-1 - Multi-user equipment approved in grant 2018/08107-2: H35 Hypoxystation with Hepa Filter, AP.EMU
• Associated scholarship(s): 20/04007-3 - Sensitization of triple-negative breast cancer to chemotherapy by the inhibition cancer stem cells self-renewal, BP.MS; 19/07723-4 - Targenting stemness as a strategy for treating triple-negative breast câncer, BP.JP

Abstract

Cancer stem-cells (CSCs) are undifferentiated cells present in heterogeneous tumors, that contribute for the maintenance of cancer through the ability to self-renew and promote tumor repopulation. CSCs do not respond to conventional treatments such as chemo and radiotherapy, that destroy highly proliferative cells and require oxygen to work. Therefore, CSCs survive quiescently, and under favorable conditions of the niche, they recapitulate the original phenotype of the tumor and promote cancer dissemination. Some master regulators of embryonic development can become inappropriately re-expressed in the adult organism during tumorigenesis to support the self-renewal of CSCs. Cripto-1 (CR1) is highly expressed in embryonic stem-cells, stimulating its growth, and inducing angiogenesis and epithelial-mesenchymal transition, which are events closely related to malignant transformation. Several types of human carcinomas express high levels of CR1, and its activity becomes specially increased under hypoxic conditions. The involvement of CR1 in reprogramming breast cancer cells into CSCs has been associated with the triple-negative subtype of this disease (TNBC), highly aggressive and resistant to treatments, most likely due its increased levels of CSCs. Considering that resistance must occur because CSCs are usually in the quiescent phase of the cell cycle and in hypoxic regions, we propose in this project new treatment strategies for TNBC that destroy CSCs and/or sensitize them to conventional therapies. By using appropriate biological models and current relevant technologies, we plan to inhibit the regulatory role of CR1 in TNBC and abrogate the quiescent state of CSCs, by inducing them to enter the cell cycle and differentiate. We believe that the association of these strategies with the reoxygenation of the hypoxic tumor microenvironment will potentially contribute for better TNBC responses to currently available therapies. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

CHENG, ROBERT Y. S.; RIDNOUR, LISA A.; WINK, ADELAIDE L.; GONZALEZ, ANA L.; FEMINO, ELISE L.; RITTSCHER, HELENE; SOMASUNDARAM, VEENA; HEINZ, WILLIAM F.; COUTINHO, LEANDRO; RANGEL, M. CRISTINA; et al. Interferon-gamma is quintessential for NOS2 and COX2 expression in ER- breast tumors that lead to poor outcome. CELL DEATH & DISEASE, v. 14, n. 5, p. 12-pg., 2023-05-11. (18/08107-2, 21/14642-0)

COUTINHO, LEANDRO DE LIMA; TORTELLI JUNIOR, THARCISIO CITRANGULO; RANGEL, MARIA CRISTINA. Sulforaphane: An emergent anti-cancer stem cell agent. FRONTIERS IN ONCOLOGY, v. 13, p. 10-pg., 2023-01-23. (18/08107-2, 21/14642-0, 20/04007-3)