---
title: "How lipid remodeling and membrane physics drive tamoxifen resistance in breast cancer"
id: "pubmed-42552972"
canonical_url: "https://medichelpline.com/clinical-feed/pubmed-42552972"
content_type: "clinical_feed_article"
specialty: "Oncology"
source_name: "PubMed / NCBI"
source_url: "https://pubmed.ncbi.nlm.nih.gov/42552972/"
doi: "10.1039/d6cp02431a"
published_at: "2026-08-26T00:00:00.000Z"
evidence_level: "Journal Article"
license: "CC-BY-NC-4.0 / Informational Use"
---
# How lipid remodeling and membrane physics drive tamoxifen resistance in breast cancer
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/pubmed-42552972
- **Specialty:** [Oncology](https://medichelpline.com/clinical-feed/oncology.md)
- **Primary Source:** PubMed / NCBI
- **Source URL:** [Original Journal Publication](https://pubmed.ncbi.nlm.nih.gov/42552972/)
- **DOI:** [10.1039/d6cp02431a](https://doi.org/10.1039%2Fd6cp02431a)
- **Published At:** 2026-08-26T00:00:00.000Z
- **Evidence Rating:** Journal Article
## Executive GIST (TL;DR)
- Drug resistance in breast cancer is linked to remodeling of the **plasma membrane** lipid composition, including loss of **lipid asymmetry** and increased **cholesterol** (CHL) and **sphingomyelin** (SM) levels. - The study used multi-scale **molecular dynamics (MD)** simulations — both all-atom and coarse-grained — on eight lipid bilayer models representing normal asymmetric (N1, N2) and cancer-mimetic symmetric (C1–C5) membranes. - Unbiased MD and **umbrella sampling** were applied to compute potential of mean force (PMF) profiles for **tamoxifen (TAM)** permeation across these bilayers. - Membrane **symmetrization** together with CHL/SM enrichment produced lipid condensation: increased bilayer thickness (D_HH), reduced area per lipid (APL), and decreased lateral fluidity. - PMF results indicate that TAM can permeate freely through base cancer models such as C2, but CHL/SM-rich, drug-resistant membranes (C3, C4) impose large energetic barriers to penetration. - In rigid, CHL/SM-enriched membranes TAM becomes strongly trapped in specific hydrophobic regions, with observed energy minima around −38 kJ mol−1, limiting drug passage into the bilayer core. - These molecular-level findings link **lipidomic alterations** to reduced TAM permeability and suggest that targeting membrane lipid metabolism or using lipid-modulating adjuvants may help overcome resistance. - The abstract does not report experimental validation, in vivo data, or specific therapeutic interventions; details beyond the simulation findings were not reported in the source.
## Clinical Analysis & Structured Key Points
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Affiliations Expand ### Affiliations * 1 Department of Biotechnology, Faculty of Biological Sciences, Alzahra University, Tehran, Iran. mzarrabi@alzahra.ac.ir. * 2 Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran. * PMID: **42552972** * DOI: [ 10.1039/d6cp02431a ](https://doi.org/10.1039/d6cp02431a) Item in Clipboard # Lipidomic adaptation and membrane physical changes underlie tamoxifen resistance in breast cancer: molecular dynamics simulation study Elahe Hoseinnia et al. Phys Chem Chem Phys. 2026. Show details Display options Display options Format Abstract PubMed PMID Phys Chem Chem Phys Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Phys+Chem+Chem+Phys%22%5Bjour%5D&sort=date&sort_order=desc) * [ Search in NLM Catalog ](https://www.ncbi.nlm.nih.gov/nlmcatalog?term=%22Phys+Chem+Chem+Phys%22%5BTitle+Abbreviation%5D) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42552972/) . 2026 Aug 26;28(33):20058-20069. doi: 10.1039/d6cp02431a. ### Authors [Elahe Hoseinnia](https://pubmed.ncbi.nlm.nih.gov/?term=Hoseinnia+E&cauthor_id=42552972)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42552972/#short-view-affiliation-1 "Department of Biotechnology, Faculty of Biological Sciences, Alzahra University, Tehran, Iran. mzarrabi@alzahra.ac.ir."), [Fatemeh Ebrahimi Tarki](https://pubmed.ncbi.nlm.nih.gov/?term=Tarki+FE&cauthor_id=42552972)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42552972/#short-view-affiliation-1 "Department of Biotechnology, Faculty of Biological Sciences, Alzahra University, Tehran, Iran. mzarrabi@alzahra.ac.ir."), [Mahboobeh Zarrabi](https://pubmed.ncbi.nlm.nih.gov/?term=Zarrabi+M&cauthor_id=42552972)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42552972/#short-view-affiliation-1 "Department of Biotechnology, Faculty of Biological Sciences, Alzahra University, Tehran, Iran. mzarrabi@alzahra.ac.ir."), [Zahra Hajimahdi](https://pubmed.ncbi.nlm.nih.gov/?term=Hajimahdi+Z&cauthor_id=42552972)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42552972/#short-view-affiliation-2 "Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.") ### Affiliations * 1 Department of Biotechnology, Faculty of Biological Sciences, Alzahra University, Tehran, Iran. mzarrabi@alzahra.ac.ir. * 2 Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran. * PMID: **42552972** * DOI: [ 10.1039/d6cp02431a ](https://doi.org/10.1039/d6cp02431a) Item in Clipboard Full text links Cite Display options Display options Format Abstract PubMed PMID ## Abstract Drug resistance in breast cancer (BC) is strongly linked to plasma membrane lipid remodeling, notably the loss of lipid asymmetry and elevated cholesterol (CHL) and sphingomyelin (SM) levels. We performed multi-scale molecular dynamics (MD) simulations on eight distinct lipid bilayer models-ranging from normal asymmetric (N1, N2) to cancer-mimetic symmetric states (C1-C5)-at all-atom and coarse-grained resolutions to investigate their impact on tamoxifen (TAM) permeation. Unbiased MD and umbrella sampling were used to compute potential of mean force (PMF) profiles. Our results indicate that membrane symmetrization and CHL/SM enrichment synergistically induce lipid condensation, increasing bilayer thickness (_D_ HH), reducing area per lipid (APL) and lateral fluidity. Crucially, PMF profiles reveal the core resistance mechanism: while TAM permeates freely through base cancer models (C2), drug-resistant CHL/SM-rich membranes (C3, C4) act as severe energetic barriers. These rigid membranes strongly trap the drug within specific hydrophobic regions (energy minima of ∼-38 kJ mol-1), limiting penetration into the bilayer core. These findings provide a molecular-level understanding of how lipidomic alterations dictate TAM permeability, suggesting that targeting membrane lipid metabolism or designing lipid-modulating adjuvants are promising therapeutic strategies to overcome drug resistance. [PubMed Disclaimer](https://pubmed.ncbi.nlm.nih.gov/disclaimer/) ## Similar articles * [ Insight into the effect of ibuprofen on the permeability of the membrane: a molecular dynamic simulation study. ](https://pubmed.ncbi.nlm.nih.gov/37982256/) Ghorbani M, Dehghan G, Allahverdi A.Ghorbani M, et al.J Biomol Struct Dyn. 2025 Jan;43(1):560-570. doi: 10.1080/07391102.2023.2283151. 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