Dataset Information

Structural, Thermodynamic, and Kinetic Traits of Antiestrogen-Compounds Selectively Targeting the Y537S Mutant Estrogen Receptor ? Transcriptional Activity in Breast Cancer Cell Lines.

ABSTRACT: The most frequently diagnosed cancers in women are the estrogen receptor (ER)-positive breast cancer subtypes, which are characterized by estrogen dependency for their growth. The mainstay of clinical treatment for this tumor relies on the modulation of ER? action or on the suppression of estrogen biosynthesis via the administration of Selective ER? Modulators/Down-regulators (SERMs/SERDs) or aromatase inhibitors, respectively. Nevertheless, de novo and acquired resistance to these therapies frequently occurs and represents a major clinical concern for patient survival. Recently, somatic mutations affecting the hormone-binding domain of ER? (i.e., Y537S, Y537N, D538G) have been associated with endocrine resistance, disease relapse and increased mortality rates. Hence, devising novel therapies against these ER? isoforms represents a daunting challenge. Here, we identified five molecules active on recurrent Y537S ER? polymorphism by employing in silico virtual screening on commercial databases of molecules, complemented by ER-transactivation and MTT assays in MCF7 and MDA-MB-231 breast cancer cells expressing wild type or mutated ER?. Among them, one molecule selectively targets Y537S ER? without inducing any cytotoxicity in breast cell lines. Multi-microseconds (4.5 ?s) of biased and unbiased molecular dynamics provided an atomic-level picture of the structural, thermodynamics (i.e., binding free energies) and the kinetic (i.e., dissociation free energy barriers) of these active ligands as compared to clinically used SERM/SERDs upon binding to wild type and distinct ER? variants (Y537S, Y537N, D538G). This study contributes to a dissection of the key molecular traits needed by drug-candidates to hamper the agonist (active)-like conformation of ER?, normally selected by those polymorphic variants. This information can be useful to discover mutant specific drug-candidates, enabling to move a step forward toward tailored approaches for breast cancer treatment.

SUBMITTER: Pavlin M

PROVIDER: S-EPMC6737084 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Structural, Thermodynamic, and Kinetic Traits of Antiestrogen-Compounds Selectively Targeting the Y537S Mutant Estrogen Receptor α Transcriptional Activity in Breast Cancer Cell Lines.

Pavlin Matic M Gelsomino Luca L Barone Ines I Spinello Angelo A Catalano Stefania S Andò Sebastiano S Magistrato Alessandra A

Frontiers in chemistry 20190904

The most frequently diagnosed cancers in women are the estrogen receptor (ER)-positive breast cancer subtypes, which are characterized by estrogen dependency for their growth. The mainstay of clinical treatment for this tumor relies on the modulation of ERα action or on the suppression of estrogen biosynthesis via the administration of Selective ERα Modulators/Down-regulators (SERMs/SERDs) or aromatase inhibitors, respectively. Nevertheless, <i>de novo</i> and acquired resistance to these therap ...[more]

PMID: 31552220

Similar Datasets

Project description:Human X-box binding protein-1 (XBP1) is an alternatively spliced transcription factor that participates in the unfolded protein response (UPR), a stress signaling pathway that allows cells to survive the accumulation of unfolded proteins in the endoplasmic reticulum lumen. We have previously demonstrated that XBP1 expression is increased in antiestrogen-resistant breast cancer cell lines, and is co-expressed with estrogen receptor alpha (ER) in breast tumors. The purpose of this study is to investigate the role of XBP1 and the UPR in estrogen and antiestrogen responsiveness in breast cancer. Overexpression of spliced XBP1 (XBP1(S)) in ER-positive breast cancer cells leads to estrogen-independent growth and reduced sensitivity to growth inhibition induced by the antiestrogens Tamoxifen and Faslodex in a manner independent of functional p53. Data from gene expression microarray analyses imply that XBP1(S) acts through regulating the expression of ER, the anti-apoptotic gene BCL2, and several other genes associated with control of the cell cycle and apoptosis. Experiment Overall Design: Total RNA was isolated from six independent cultures (cell populations grown on different days from different stocks); three from MCF7/XBP1 cultures and three from the vector control cultures. MIAME 1.1 compliant data were collected as recommended by the Microarray Gene Expression Data (MGED) Society. RNA concentrations were determined by comparing the optical density ratios (260:280 nm) , and data on RNA quality was obtained using an Agilent 2100 Bioanalyzer and RNA 6000 LabChip kits (Agilent Technologies, New Castle, DE). RNA quality was assessed by visual inspection of the electropherograms from the Bioanalyzer data, and by the calculated RNA integrity numbers (RIN) and Degradometer values . Only high quality total RNA was labeled and hybridized to U133A Affymetrix GeneChips using manufacturer recommended procedures (Affymetrix, Santa Clara, CA). Standard “spiked-in” controls also were included in each hybridization.

Dataset Information

Structural, Thermodynamic, and Kinetic Traits of Antiestrogen-Compounds Selectively Targeting the Y537S Mutant Estrogen Receptor ? Transcriptional Activity in Breast Cancer Cell Lines.

Publications

Structural, Thermodynamic, and Kinetic Traits of Antiestrogen-Compounds Selectively Targeting the Y537S Mutant Estrogen Receptor α Transcriptional Activity in Breast Cancer Cell Lines.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets