Discovery of a multi-target compound for estrogen receptor-positive (ER+) breast cancer: Involvement of aromatase and ERs

• Type: Article in International Scientific Journal
• Date: 2021

Authors

Almeida, CF (Author) Other; Teixeira, N (Author) Other; Oliveira, A (Author) Other; Augusto, TV (Author) Other; Georgina Correia da Silva (Author) FFUP; Ramos, MJ (Author) FCUP; Pedro A Fernandes (Author) FCUP; Amaral, C (Author) Other

Journal

Title: Biochimie

Vol. 181

Pages: 65-76

ISSN: 0300-9084

Publisher: Elsevier

Indexing

ISI Web of Knowledge - 14 Citations

Scopus - 15 Citations

Other information

Authenticus ID: P-00T-69W

DOI: 10.1016/j.biochi.2020.11.023

Abstract (EN): Despite intense research, breast cancer remains the leading cause of cancer-related death in women worldwide, being estrogen receptor-positive (ER+) the most common subtype. Nowadays, aromatase inhibitors (AIs), the selective estrogen receptor modulator (SERM) tamoxifen and the selective estrogen receptor down-regulator (SERD) fulvestrant are used as therapeutic options for ER+ breast cancer, since they interfere directly with the production of estrogens and with the activation of estrogen-dependent signaling pathways. Despite the success of these treatments, the occurrence of resistance limits their clinical efficacy, demanding the development of novel therapies. Recently, multi-target compounds emerged as promising therapeutic strategies for ER+ breast cancer, as they can potentially modulate several important targets simultaneously. In line with this, in this work, the anti-cancer properties and multi-target action of 1,1-Bis(4-hydroxyphenyl)-2-phenylbut-1-ene, tamoxifen bisphenol (1,1-BHPE), were evaluated in an ER+ breast cancer cell model (MCF-7aro cells). Molecular docking analysis predicted that 1,1-BHPE was able to bind to aromatase, ER alpha and ER beta. In vitro studies showed that, although it did not present anti-aromatase activity, 1,1-BHPE reduced aromatase protein levels and interfered with ER alpha and ERb signaling pathways, acting as an ER alpha antagonist and inducing ER beta up-regulation. Through these mechanisms, 1,1-BHPE was able to impair breast cancer growth and induce apoptosis. This represents an important therapeutic advantage because the main players responsible for estrogen production and signaling are modulated by a single compound. To the best of our knowledge, this is the first study describing the anti-cancer properties of 1,1-BHPE as a multi-target compound specific for ER+ breast cancer.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 12