Molecular mechanisms and allostery in estrogen receptor alpha using bond-to- bond propensities (360G-Wellcome-215360_Z_19_Z)

Breast cancer (BC) is the most common cancer in women worldwide. Estrogen receptor alpha (ERα) is the main driver in BC development and progression, and drugs inhibiting ERα are the main focus of treatment in BC. Current chemotherapies based on inhibiting ERα become ineffective when recurrent tumours develop resistance against anti-estrogens. Our work aims at finding new ways of disrupting the impact of ERα by investigating the protein on a structural level. For this, we evaluate the protein as a network and define every atom in the structure as a node, which allows us to use mathematical methods from graph-theory to investigate atomistic details. These methods have allowed us to identify novel allosteric sites and reveal new functional properties in many proteins. I want to understand the mechanistic details of ERα inhibition in cancer and the signalling paths used within the protein structure. Following on from there, I want to explore how mutated amino acids in the context of resistance manage to re-introduce functionality to the protein. By defining key allosteric sites in wild-type and mutant ERα, I aim to identify new target sites and important residues for the development of new anti-estrogens which can be used in cancer treatment.