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Profiling of Estrogen-regulated MicroRNAs in Breast Cancer Cells
Published on: February 21, 2014
Benzimidazoles diminish ERE transcriptional activity and cell growth in breast cancer cells
Florastina Payton-Stewart1, Syreeta L Tilghman2, LaKeisha G Williams3
1Department of Chemistry, College of Arts and Sciences, Xavier University of Louisiana, New Orleans, LA, USA.
Abstract:
Estrogen receptors (ERα and ERβ) are members of the nuclear receptor superfamily. They regulate the transcription of estrogen-responsive genes and mediate numerous estrogen related diseases (i.e., fertility, osteoporosis, cancer, etc.). As such, ERs are potentially useful targets for developing therapies and diagnostic tools for hormonally responsive human breast cancers. In this work, two benzimidazole-based sulfonamides originally designed to reduce proliferation in prostate cancer, have been evaluated for their ability to modulate growth in estrogen dependent and independent cell lines (MCF-7 and MDA-MB 231) using cell viability assays. The molecules reduced growth in MCF-7 cells, but differed in their impact on the growth of MDA-MB 231 cells. Although both molecules reduced estrogen response element (ERE) transcriptional activity in a dose dependent manner, the contrasting activity in the MDA-MB-231 cells seems to suggest that the molecules may act through alternate ER-mediated pathways. Further, the methyl analog showed modest selectivity for the ERβ receptor in an ER gene expression array panel, while the naphthyl analog did not significantly alter gene expression. The molecules were docked in the ligand binding domains of the ERα-antagonist and ERβ-agonist crystal structures to evaluate the potential of the molecules to interact with the receptors. The computational analysis complimented the results obtained in the assay of transcriptional activity and gene expression suggesting that the molecules upregulate ERβ activity while down regulating that of ERα.
Insights
Two novel benzimidazole-based sulfonamides show potential for breast cancer therapy by modulating estrogen receptors (ERs). These compounds impact ERα and ERβ activity, offering new avenues for treating hormone-responsive cancers.
Area of Science:
- Endocrinology
- Molecular Biology
- Medicinal Chemistry
Background:
- Estrogen receptors (ERα and ERβ) are crucial nuclear receptors regulating gene transcription and involved in various diseases, including hormone-responsive breast cancers.
- Targeting ERs is a key strategy for developing therapies and diagnostic tools for breast cancer.
- Benzimidazole-based sulfonamides, initially developed for prostate cancer, were investigated for their effects on estrogen receptor activity.
Purpose of the Study:
- To evaluate the ability of two benzimidazole-based sulfonamides to modulate cell growth in estrogen-dependent (MCF-7) and estrogen-independent (MDA-MB 231) breast cancer cell lines.
- To investigate the impact of these compounds on estrogen response element (ERE) transcriptional activity and ERβ receptor selectivity.
- To computationally assess the interaction of these molecules with ERα and ERβ ligand-binding domains.
Main Methods:
- Cell viability assays were performed on MCF-7 and MDA-MB 231 cell lines.
- Estrogen response element (ERE) transcriptional activity was measured.
- An ER gene expression array panel was used to assess receptor selectivity.
- Molecular docking simulations were conducted on ERα and ERβ crystal structures.
Main Results:
- Both compounds reduced proliferation in MCF-7 cells, with differential effects on MDA-MB 231 cells.
- The molecules dose-dependently reduced ERE transcriptional activity.
- The methyl analog exhibited modest selectivity for ERβ, while the naphthyl analog did not significantly alter gene expression.
- Computational analysis suggested that the molecules upregulate ERβ activity and downregulate ERα activity.
Conclusions:
- Benzimidazole-based sulfonamides demonstrate potential as modulators of estrogen receptor activity.
- These compounds may act through distinct ER-mediated pathways, offering therapeutic potential for hormone-responsive breast cancers.
- Further investigation into their selective ERα downregulation and ERβ upregulation is warranted for drug development.
