Marine compounds that induce DNA damage and inhibit TBX2 as a new strategy to treat breast cancer

• Grant number: 18/08400-1
• Support Opportunities: Regular Research Grants
• Duration: September 01, 2018 - August 31, 2022
• Field of knowledge: Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
• Convênio/Acordo: National Research Foundation, South Africa
• Mobility Program: SPRINT - Projetos de pesquisa - Mobilidade
• Principal Investigator: Leticia Veras Costa Lotufo
• Grantee: Leticia Veras Costa Lotufo
• Principal researcher abroad: Sharon Prince
• Institution abroad: University of Cape Town (UCT), South Africa
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 15/17177-6 - Integrative approach on the sustainable prospection of marine natural products: from diversity to anticancer compounds, AP.BTA.TEM

Abstract

Breast cancer is the most common malignancy in women globally. In general, 90% of primary and 50% of metastatic breast cancers respond to systemic agents initially but resistance to therapy is common. Tumours develop resistance to DNA-damaging chemotherapeutic agents, in part, due to enhanced DNA repair capacity. Combination therapies that induce DNA damage and disrupt the DNA damage repair (DDR) process may therefore prove to be effective against such tumours. In this regard, we are interested in the transcription factor, TBX2, which is overexpressed in several cancers including breast cancer. The Prince lab has shown that TBX2 functions as a potent growth-promoting factor in metastatic breast cancer cells and confers resistance to the widely used DNA damaging drug cisplatin. Importantly, depleting TBX2 sensitised cisplatin resistant breast cancer cells to this drug by disrupting the DDRsignalling pathway. These results suggest that a promising anti-cancer strategy would be to induce the DNA damage response and inhibit TBX2. Interestingly, BRCA1, a key DDR gene is mutated in familial breast cancers which show resistance to platinum based compounds and PARP inhibitors. TBX2 is preferentially amplified and over-expressed in BRCA1 defective breast tumours and we therefore expect that TBX2 inhibitors would be effective therapeutic agents against these highly drug resistant cells. The Costa-Lotufo lab has shown, using affinity chromatography, that TBX2 interacts with chromomycin A2, a marine compound that intercalates with DNA. This suggests that chromomycin A2 may interfere with the mechanisms involved in breast cancer drug resistance by inducing DNA lesions and sequestering TBX2. As a new strategy to treat breast cancer we therefore propose to test the anti-cancer activity of chromomycin A2 and similar marine compounds, capable of inducing DNA lesions and inhibiting TBX2, in breast cancer cells. (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)

SAHM, BIANCA DEL B.; PERES, JADE; REZENDE-TEIXEIRA, PAULA; SANTOS, EVELYNE A.; BRANCO, PAOLA C.; BAUERMEISTER, ANELIZE; KIMANI, SERAH; MOREIRA, EDUARDA A.; BISI-ALVES, RENATA; BELLIS, CLAIRE; et al. Targeting the Oncogenic TBX2 Transcription Factor With Chromomycins. FRONTIERS IN CHEMISTRY, v. 8, MAR 3 2020. (18/24865-4, 15/17177-6, 19/02008-5, 18/08400-1, 17/09022-8)