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

• Published in: Biochimie 2021-02, Vol.181, p.65-76
• Main Authors: Almeida, Cristina Ferreira, Teixeira, Natércia, Oliveira, Ana, Augusto, Tiago V., Correia-da-Silva, Georgina, Ramos, Maria João, Fernandes, Pedro Alexandrino, Amaral, Cristina
• Format: Article
• Language: English
• Subjects: Aromatase; Endocrine therapy; Estrogen receptor-positive breast cancer; Estrogen receptors; Molecular docking; Multi-target compounds
• ISSN: 0300-9084; 1638-6183
• DOI: 10.1016/j.biochi.2020.11.023

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, ERα and ERβ. In vitro studies showed that, although it did not present anti-aromatase activity, 1,1-BHPE reduced aromatase protein levels and interfered with ERα and ERβ signaling pathways, acting as an ERα antagonist and inducing ERβ 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. •This is the first in vitro study describing the anti-cancer properties of 1,1-Bis(4-hydroxyphenyl)-2-phenylbut-1-ene (1,1-BHPE), also known as tamoxifen bisphenol.•1,1-BHPE impaired growth and induced apoptosis of ER+ breast cancer cells.•This compound targets aromatase by reducing its protein levels on cancer cells.•It also modulates ER signalling pathways, by acting as an ERα antagonist and inducing ERβ up-regulation.•1,1-BHPE act as a specific multi-target compound in ER+ breast cancer cells.