ERα-targeted endocrine therapy, resistance and the role of GPER.

Endocrine therapy is an effective option for the treatment of estrogen receptor alpha (ERα)-positive breast cancers. Unfortunately, a large fraction of women relapse with endocrine-resistant tumors. The presence of constitutively active ERα mutants, found in a subset of relapse tumors, is thought to be an important endocrine resistance mechanism and has prompted the search for more effective anti-hormone drugs that can effectively inhibit these mutant versions of the receptor. The G protein-coupled estrogen receptor (GPER) is also thought to contribute to the development of endocrine resistance, in part, due to its activation by clinically used selective estrogen receptor modulators and downregulators (SERMs/SERDs). Therefore, next-generation drugs should be screened for potential activity towards GPER. Here, we highlight the need for truly ERα-selective SERMs and SERDs that do not cross-react with GPER for the treatment of ERα-positive breast cancers.

Pepermans RA ，Prossnitz ER 《-》

MIBE acts as antagonist ligand of both estrogen receptor α and GPER in breast cancer cells.

Lappano R ，Santolla MF ，Pupo M ，Sinicropi MS ，Caruso A ，Rosano C ，Maggiolini M ... -  《-》

Estrogen-mediated inactivation of FOXO3a by the G protein-coupled estrogen receptor GPER.

Zekas E ，Prossnitz ER 《BMC CANCER》

GPER-1/GPR30 a novel estrogen receptor sited in the cell membrane: therapeutic coupling to breast cancer.

Molina L ，Figueroa CD ，Bhoola KD ，Ehrenfeld P ... -  《-》

Antiestrogens in combination with immune checkpoint inhibitors in breast cancer immunotherapy.

Breast cancers (BCs) with expression of estrogen receptor-alpha (ERα) occur in more than 70% of newly-diagnosed patients in the U.S. Endocrine therapy with antiestrogens or aromatase inhibitors is an important intervention for BCs that express ERα, and it remains one of the most effective targeted treatment strategies. However, a substantial proportion of patients with localized disease, and essentially all patients with metastatic BC, become resistant to current endocrine therapies. ERα is present in most resistant BCs, and in many of these its activity continues to regulate BC growth. Fulvestrant represents one class of ERα antagonists termed selective ER downregulators (SERDs). Treatment with fulvestrant causes ERα down-regulation, an event that helps overcome several resistance mechanisms. Unfortunately, full antitumor efficacy of fulvestrant is limited by its poor bioavailability in clinic. We have designed and tested a new generation of steroid-like SERDs. Using ERα-positive BC cells in vitro, we find that these compounds suppress ERα protein levels with efficacy similar to fulvestrant. Moreover, these new SERDs markedly inhibit ERα-positive BC cell transcription and proliferation in vitro even in the presence of estradiol-17β. In vivo, the SERD termed JD128 significantly inhibited tumor growth in MCF-7 xenograft models in a dose-dependent manner (P < 0.001). Further, our findings indicate that these SERDs also interact with ER-positive immune cells in the tumor microenvironment such as myeloid-derived suppressor cells (MDSC), tumor infiltrating lymphocytes and other selected immune cell subpopulations. SERD-induced inhibition of MDSCs and concurrent actions on CD8+ and CD4 + T-cells promotes interaction of immune checkpoint inhibitors with BC cells in preclinical models, thereby leading to enhanced tumor killing even among highly aggressive BCs such as triple-negative BC that lack ERα expression. Since monotherapy with immune checkpoint inhibitors has not been effective for most BCs, combination therapies with SERDs that enhance immune recognition may increase immunotherapy responses in BC and improve patient survival. Hence, ERα antagonists that also promote ER downregulation may potentially benefit patients who are unresponsive to current endocrine therapies.

Márquez-Garbán DC ，Deng G ，Comin-Anduix B ，Garcia AJ ，Xing Y ，Chen HW ，Cheung-Lau G ，Hamilton N ，Jung ME ，Pietras RJ ... -  《-》