pH and the Breast Cancer Recurrent Mutation D538G Affect the Process of Activation of Estrogen Receptor alpha

Author(s)

de Oliveira, Vinicius M. ; Dias, Marieli M. G. ; Avelino, Thayna M. ; Videira, Natalia B. ; da Silva, Fernando B. ; Doratioto, Tabata R. ; Whitford, Paul C. ; Leite, Vitor B. P. ; Figueira, Ana Carolina M.

• Document type: Journal article
• Source: BIOCHEMISTRY; v. 61, n. 6, p. 9-pg., 2022-02-21.

Abstract

Estrogen receptor alpha (ER alpha) is a regulatory protein that can access a set of distinct structural configurations. ER alpha undergoes extensive remodeling as it interacts with different agonists and antagonists, as well as transcription activation and repression factors. Moreover, breast cancer tumors resistant to hormone therapy have been associated with the imbalance between the active and inactive ER alpha states. Cancer-activating mutations in ER alpha play a crucial role in this imbalance and can promote the progression of cancer. However, the rate of this progression can also be increased by dysregulated pH in the tumor microenvironment. Many molecular aspects of the process of activation of ER alpha that can be affected by these pH changes and mutations are still unclear. Thus, we applied computational and experimental techniques to explore the activation process dynamics of ER for environments with different pHs and in the presence of one of the most recurrent cancer-activating mutations, D538G. Our results indicated that the effect of the pH increase associated with the D538G mutation promoted a robust stabilization of the active state of ER. We were also able to determine the main protein regions that have the most potential to influence the activation process under different pH conditions, which may provide targets of future therapeutics for the treatment of hormone-resistant breast cancer tumors. Finally, the approach used here can be applied for proteins associated with the proliferation of other cancer types, which can also have their function affected by small pH changes. (AU)

• FAPESP's process: 18/11614-3 - Effect of pH and Cancer-Activating Mutations on Functional Transition of Estrogen Receptor
• Grantee: Vinicius Martins de Oliveira
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 19/10274-7 - Study of the PPARy-coregulators interactions and its relationship with adipogenesis and insulin resistance
• Grantee: Marieli Mariano Gonçalves Dias
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 14/50739-5 - Elucidating the role of disorder during biomolecular fuction
• Grantee: Vitor Barbanti Pereira Leite
• Support Opportunities: Regular Research Grants
• FAPESP's process: 16/02348-2 - STRUCTURAL STUDIES OF THE INTERACTION OF NORMAL AND PATHOLOGICAL RAR AND THR WITH COREPRESSORS.
• Grantee: Tábata Renée Doratioto
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 19/22540-3 - Studies of energy landscapes of biological macromolecules
• Grantee: Vitor Barbanti Pereira Leite
• Support Opportunities: Regular Research Grants
• FAPESP's process: 16/19766-1 - Biological macromolecules energy landscapes with applications in biotechnology and in biomedicine
• Grantee: Vitor Barbanti Pereira Leite
• Support Opportunities: Regular Research Grants
• FAPESP's process: 19/14465-1 - Dissection of PPAR gama modulation mechanisms as target to treat diabetes and obesity development
• Grantee: Ana Carolina Migliorini Figueira
• Support Opportunities: Regular Research Grants