The Interplay of GPER1 with 17β-Aminoestrogens in the Regulation of the Proliferation of Cervical and Breast Cancer Cells: A Pharmacological Approach

Int J Environ Res Public Health. 2022 Sep 28;19(19):12361. doi: 10.3390/ijerph191912361.


The G-protein-coupled receptor for estrogen (GPER1) is a transmembrane receptor involved in the progression and development of various neoplasms whose ligand is estradiol (E2). 17β-aminoestrogens (17β-AEs) compounds, analogs to E2, are possible candidates for use in hormone replacement therapy (HRT), but our knowledge of their pharmacological profile is limited. Thus, we explored the molecular recognition of GPER1 with different synthetic 17β-AEs: prolame, butolame, and pentolame. We compared the structure and ligand recognition sites previously reported for a specific agonist (G1), antagonists (G15 and G36), and the natural ligand (E2). Then, the biological effects of 17β-AEs were analyzed through cell viability and cell-cycle assays in two types of female cancer. In addition, the effect of 17β-AEs on the phosphorylation of the oncoprotein c-fos was evaluated, because this molecule is modulated by GPER1. Molecular docking analysis showed that 17β-AEs interacted with GPER1, suggesting that prolame joins GPER1 in a hydrophobic cavity, similarly to G1, G15, and E2. Prolame induced cell proliferation in breast (MCF-7) and cervical cancer (SIHA) cells; meanwhile, butolame and pentolame did not affect cell proliferation. Neither 17β-AEs nor E2 changed the activation of c-fos in MCF-7 cells. Meanwhile, in SIHA cells, E2 and 17β-AEs reduced c-fos phosphorylation. Thus, our data suggest that butolame and pentolame, but not prolame, could be used for HRT without presenting a potential risk of inducing breast- or cervical-cancer-cell proliferation. The novelty of this work lies in its study of compound analogs to E2 that may represent important therapeutic strategies for women in menopause, with non-significant effects on the cell viability of cancer cells. The research focused on the interactions of GPER1, a molecule recently associated with promoting and maintaining various neoplasms.

Keywords: 17β-aminoestrogens (17β-AEs); G-protein-coupled estrogen receptor (GPER1); cancer cells; cell viability; molecular docking.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Alcohols
  • Breast Neoplasms* / drug therapy
  • Cell Proliferation
  • Estradiol / pharmacology
  • Estrenes
  • Estrogens / pharmacology
  • Female
  • Humans
  • Ligands
  • Molecular Docking Simulation
  • Oncogene Proteins / pharmacology
  • Receptors, Estrogen / metabolism*
  • Receptors, G-Protein-Coupled / metabolism*


  • Amino Alcohols
  • Estrenes
  • Estrogens
  • GPER1 protein, human
  • Ligands
  • Oncogene Proteins
  • Receptors, Estrogen
  • Receptors, G-Protein-Coupled
  • butolame
  • pentolame
  • Estradiol

Grants and funding

This research was funded by Proyecto PAPIIT IN200222, Proyecto FM/DI/009/2021 and FM/DI/036/2020, approved by División de Investigación de la Facultad de Medicina UNAM, and Budget granted by Facultad de Medicina, UNAM.