Tamoxifen bisphenol: a modulator of ERβ in estrogen receptor-positive breast cancer

Introduction: Despite efforts, breast cancer remains the main cause of cancer-related death in women worldwide, being estrogen receptor-positive (ER⁺) the most common subtype. In this type of cancer, while ERα is responsible for the growth/survival of the tumor, ERβ displays anti-proliferative actions, counteracting ERα effects. Thus, ERβ modulators may represent a great advantage for breast cancer treatment.

Aim: Considering that Tamoxifen Bisphenol (TAM-Bis), a tamoxifen metabolite, can act as an ERα antagonist, our goal is to investigate whether this compound can also modulate ERβ.

Methods: Through molecular docking analysis, it was addressed the ability of TAM-Bis to bind to ERβ. HFF-1 and MCF-7aro cells were used to evaluate the effects of TAM-Bis. To confirm the involvement of ERβ, the down-regulator PHTPP was used. The effects of TAM-Bis on ERβ protein levels were also investigated by Western-Blot.

Results: Molecular docking results pointed that TAM-Bis can bind to ERβ. Moreover, this compound only decreased the viability of breast cancer cells, MCF-7aro, being this behavior reverted by PHTPP. In addition, TAM-Bis induced an up-regulation of ERβ.

Discussion: Our results clearly demonstrated that, besides being an ERα antagonist, TAM-Bis is an ERβ up-regulator. This is very favorable for better prognosis, since ERβ inhibits the transcriptional activity of ERα and decreases the sensitivity of breast cancer cells to estrogens, impairing tumor growth.

Acknowledgments: The authors are grateful to Fundação para a Ciência e Tecnologia (FCT) for CA Post-doc grant (SFRH/BPD/98304/2013), Tiago Augusto PhD grant (BD/128333/2017) and for the financial support ((UIDB/04378/2020).