Breast Cancer Progression and Phytoestrogen Interactions with Estrogen Receptors

Balcazar Lopez, C. 2017. Breast Cancer Progression and Phytoestrogen Interactions with Estrogen Receptors. PhD thesis University of Westminster Biomedical Sciences

TitleBreast Cancer Progression and Phytoestrogen Interactions with Estrogen Receptors
TypePhD thesis
AuthorsBalcazar Lopez, C.
Abstract

Breast cancer is one of the most common diseases affecting women and approximately 1.3 million females are diagnosed each year with this disease worldwide. Breast cancer is a multi-factorial disease and it is difficult to predict or control the physiopathology, to date one of the major risk factors alongside the patient’s genetic background is life time exposure to estrogen. Understanding the estrogen receptor (ER) has been a milestone in elucidating breast cancer biology, leading to advances in disease management. Alongside this, evidence from epidemiological studies suggests that dietary consumption of phytoestrogens may modulate disease progression. This study hypothesises that the interaction between some phytoestrogens (present in the pre-diagnosis diet or in the new diet adopted by breast cancer patients) and specific ER isoforms displayed in breast tumours influences the action of synthetic and endogenous estrogen in breast cancer cells. This study aimed to understand the interaction between estrogen, hormone drugs and phytoestrogens on the ER. In silico modelling of the ER focused on the wild type isoforms ERα and ERβ and different ligands (SWISS MODEL and docked through AutoDock Vina). Subsequently, isoforms of ERα and ERβ and different ligands (E1, E2, E3, PE, Tamoxifen, ICI 182,780) were modelled and tested by docking against the same set of ligands (E1, E2, E3, PE, Tamoxifen, ICI 182,780).

The system described here highlighted the main amino acid residues of the LBD of ERα and ERβ along with ligand interactions for both agonists and antagonists, described in previous X-ray crystallography experiments. All of the phytoestrogens studied using AutoDock Vina interacted with the hormone binding site of both ERα and ERβ, due the phenolic ring of the studied structure which favoured the interaction with the hydrophobic environment of LBD amino acids. All of the dietary phytoestrogens showed lower binding affinity (<9.1 Kcal/mol) compared with estradiol (-10.6 Kcal/mol) in all the isoforms and isotypes studied, suggesting that phytoestrogens should not displace estradiol from the LBD, however it remains unclear if PE can act as an agonist compound in the ER pathways. Also, some phytoestrogens appeared to have greater affinity to the ERα and ERβ than Tamoxifen (antagonist models), but it is uncertain as to whether the resulting structure will interfere with subsequent interactions. Further laboratory experiments will be necessary to understand the impact of the PE in the ERs structure and the respective role in the ER pathway.

The data from this computer modelling approach has provided an insight into the interactions between endogenous estrogens, drugs, phytoestrogens and ER. The in silico studies generated a system that recapitulated data obtained by other research groups (experimentally) and will be of value as a screening tool for further studies of new drugs and exogenous estrogens and their potential role in ER-induced breast cancer pathophysiology.

Year2017
FileLopez_Carlos_thesis.pdf

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Permalink - https://westminsterresearch.westminster.ac.uk/item/q3834/breast-cancer-progression-and-phytoestrogen-interactions-with-estrogen-receptors


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