---
title: "Pemetrexed Stabilizes BRCA1 and Enhances Radiosensitivity in Triple‑Negative Breast Cancer"
id: "pubmed-42757486"
canonical_url: "https://medichelpline.com/clinical-feed/pubmed-42757486"
content_type: "clinical_feed_article"
specialty: "Oncology"
source_name: "PubMed / NCBI"
source_url: "https://pubmed.ncbi.nlm.nih.gov/42757486/"
doi: "10.3892/or.2026.9194"
published_at: "2026-09-18T12:00:00.000Z"
evidence_level: "Journal Article"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Pemetrexed Stabilizes BRCA1 and Enhances Radiosensitivity in Triple‑Negative Breast Cancer
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/pubmed-42757486
- **Specialty:** [Oncology](https://medichelpline.com/clinical-feed/oncology.md)
- **Primary Source:** PubMed / NCBI
- **Source URL:** [Original Journal Publication](https://pubmed.ncbi.nlm.nih.gov/42757486/)
- **DOI:** [10.3892/or.2026.9194](https://doi.org/10.3892%2For.2026.9194)
- **Published At:** 2026-09-18T12:00:00.000Z
- **Evidence Rating:** Journal Article
## Executive GIST (TL;DR)
- BRCA1 is a multifunctional tumor suppressor regulating **homologous recombination repair**, chromatin remodeling, cell cycle and apoptosis; reduced BRCA1 protein—often from accelerated proteasomal degradation—is implicated in aggressive and therapy‑resistant **triple‑negative breast cancer (TNBC)**. - The study screened FDA‑approved drugs in silico and identified **pemetrexed (Peme)** as a candidate that modulates BRCA1 protein homeostasis in TNBC models. - Experimental approaches included **immunoblotting**, ubiquitin pull‑down, cycloheximide chase, BRCA1 deletion mutants, in silico docking, apoptosis assays, BRCA1 knockdown, in vitro cytotoxicity/radiosensitization assays and TNBC xenograft experiments. - Pemetrexed increased BRCA1 protein abundance without changing BRCA1 mRNA, consistent with **post‑translational regulation** via suppressed ubiquitin‑mediated proteasomal degradation and reduced BRCA1 turnover. - In silico docking and deletion mutant data suggested involvement of the **BRCA1 C‑terminal domain** in the pemetrexed effect on stability. - Stabilized BRCA1 increased apoptotic responses to treatment, while BRCA1 knockdown attenuated those effects, linking BRCA1 stabilization to functional chemosensitization. - Combined pemetrexed and radiation produced greater cytotoxicity in vitro and inhibited tumor growth in TNBC xenografts, demonstrating a **radiosensitizing** effect associated with BRCA1 stabilization. - The authors propose pharmacological restoration of BRCA1 stability as a potential strategy to overcome therapeutic resistance in BRCA1‑deficient or functionally compromised breast cancer. - Specific numerical data, dosing regimens, statistical measures, and detailed experimental parameters were not reported in the abstract and therefore are not available from the source provided.
## Clinical Analysis & Structured Key Points
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Epub 2026 Sep 18. # Pemetrexed increases BRCA1 protein stability and sensitizes TNBC cells to radiotherapy [Hee Jin](https://pubmed.ncbi.nlm.nih.gov/?term=Jin+H&cauthor_id=42757486)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42757486/#full-view-affiliation-1 "Graduate School of Pharmaceutical Sciences and College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea."), [Kyung-Hwa Jeon](https://pubmed.ncbi.nlm.nih.gov/?term=Jeon+KH&cauthor_id=42757486)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42757486/#full-view-affiliation-1 "Graduate School of Pharmaceutical Sciences and College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea."), [Chaerin Kang](https://pubmed.ncbi.nlm.nih.gov/?term=Kang+C&cauthor_id=42757486)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42757486/#full-view-affiliation-1 "Graduate School of Pharmaceutical Sciences and College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea."), [Joohyun Lee](https://pubmed.ncbi.nlm.nih.gov/?term=Lee+J&cauthor_id=42757486)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42757486/#full-view-affiliation-1 "Graduate School of Pharmaceutical Sciences and College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea."), [Yeonjin Lee](https://pubmed.ncbi.nlm.nih.gov/?term=Lee+Y&cauthor_id=42757486)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42757486/#full-view-affiliation-2 "Innovative BioPharmChem Convergence Education and Research Program, Ewha Womans University, Seoul 03760, Republic of Korea."), [Youngjoo Kwon](https://pubmed.ncbi.nlm.nih.gov/?term=Kwon+Y&cauthor_id=42757486)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42757486/#full-view-affiliation-1 "Graduate School of Pharmaceutical Sciences and College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea."), [Yun-Sil Lee](https://pubmed.ncbi.nlm.nih.gov/?term=Lee+YS&cauthor_id=42757486)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42757486/#full-view-affiliation-1 "Graduate School of Pharmaceutical Sciences and College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea.") Affiliations Expand ### Affiliations * 1 Graduate School of Pharmaceutical Sciences and College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea. * 2 Innovative BioPharmChem Convergence Education and Research Program, Ewha Womans University, Seoul 03760, Republic of Korea. * PMID: **42757486** * DOI: [ 10.3892/or.2026.9194 ](https://doi.org/10.3892/or.2026.9194) Item in Clipboard # Pemetrexed increases BRCA1 protein stability and sensitizes TNBC cells to radiotherapy Hee Jin et al. Oncol Rep. 2026 Nov. Show details Display options Display options Format Abstract PubMed PMID Oncol Rep Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Oncol+Rep%22%5Bjour%5D&sort=date&sort_order=desc) * [ Search in NLM Catalog ](https://www.ncbi.nlm.nih.gov/nlmcatalog?term=%22Oncol+Rep%22%5BTitle+Abbreviation%5D) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42757486/) . 2026 Nov;56(5):188. doi: 10.3892/or.2026.9194. Epub 2026 Sep 18. ### Authors [Hee Jin](https://pubmed.ncbi.nlm.nih.gov/?term=Jin+H&cauthor_id=42757486)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42757486/#short-view-affiliation-1 "Graduate School of Pharmaceutical Sciences and College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea."), [Kyung-Hwa Jeon](https://pubmed.ncbi.nlm.nih.gov/?term=Jeon+KH&cauthor_id=42757486)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42757486/#short-view-affiliation-1 "Graduate School of Pharmaceutical Sciences and College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea."), [Chaerin Kang](https://pubmed.ncbi.nlm.nih.gov/?term=Kang+C&cauthor_id=42757486)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42757486/#short-view-affiliation-1 "Graduate School of Pharmaceutical Sciences and College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea."), [Joohyun Lee](https://pubmed.ncbi.nlm.nih.gov/?term=Lee+J&cauthor_id=42757486)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42757486/#short-view-affiliation-1 "Graduate School of Pharmaceutical Sciences and College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea."), [Yeonjin Lee](https://pubmed.ncbi.nlm.nih.gov/?term=Lee+Y&cauthor_id=42757486)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42757486/#short-view-affiliation-2 "Innovative BioPharmChem Convergence Education and Research Program, Ewha Womans University, Seoul 03760, Republic of Korea."), [Youngjoo Kwon](https://pubmed.ncbi.nlm.nih.gov/?term=Kwon+Y&cauthor_id=42757486)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42757486/#short-view-affiliation-1 "Graduate School of Pharmaceutical Sciences and College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea."), [Yun-Sil Lee](https://pubmed.ncbi.nlm.nih.gov/?term=Lee+YS&cauthor_id=42757486)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42757486/#short-view-affiliation-1 "Graduate School of Pharmaceutical Sciences and College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea.") ### Affiliations * 1 Graduate School of Pharmaceutical Sciences and College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea. * 2 Innovative BioPharmChem Convergence Education and Research Program, Ewha Womans University, Seoul 03760, Republic of Korea. * PMID: **42757486** * DOI: [ 10.3892/or.2026.9194 ](https://doi.org/10.3892/or.2026.9194) Item in Clipboard Cite Display options Display options Format Abstract PubMed PMID ## Abstract BRCA1 is a multifunctional tumor suppressor that orchestrates homologous recombination repair, chromatin remodeling, cell cycle control and apoptosis. Although pathogenic BRCA1 mutations are relatively uncommon, decreased BRCA1 protein expression, which is typically driven by accelerated proteasomal degradation, is implicated in aggressive breast cancer (BC), particularly triple‑negative (TN)BC. These mutations may modulate therapeutic response to DNA‑damaging agents. Given the absence of clinically available strategies to restore BRCA1 stability, the present study evaluated whether pemetrexed (Peme), a multitargeted antifolate identified through an _in silico_ US Food and Drug Administration‑approved drug screen, modulates BRCA1 protein homeostasis in TNBC models. BRCA1 protein abundance, ubiquitination and turnover were assessed using immunoblotting, ubiquitin pull‑down and cycloheximide chase analyses and BRCA1 domain mutants. Functional consequences of Peme treatment were measured by apoptosis assay and BRCA1‑dependent signaling readouts. The radiosensitizing effect of Peme was evaluated _in vitro_ and validated in TNBC xenografts. Peme increased BRCA1 protein levels without altering BRCA1 mRNA, indicating post‑translational regulation. Mechanistically, _in silico_ docking and BRCA1 deletion mutant analyses suggested that the BRCA1 C‑terminal domain may contribute to the effect of Peme on BRCA1 stability, suppressing ubiquitin‑mediated proteasomal degradation and resulting in protein stabilization. Stabilized BRCA1 enhanced apoptotic responses, whereas BRCA1 knockdown attenuated these effects. Combined Peme‑radiation treatment significantly potentiated cytotoxicity _in vitro_ and inhibited tumor growth _in vivo_ , demonstrating a radiosensitizing effect linked to BRCA1 stabilization. Collectively, these findings identified Peme as a BRCA1‑stabilizing agent that enhances therapeutic response to radiation in TNBC. Pharmacological restoration of BRCA1 stability represents a promising strategy to overcome therapeutic resistance in BRCA1‑deficient or functionally compromised BC. **Keywords:** BRCA1; pemetrexed; protein stability; radiosensitization; triple‑negative breast cancer. [PubMed Disclaimer](https://pubmed.ncbi.nlm.nih.gov/disclaimer/) ## Similar articles * [ Radiosensitization with combined use of olaparib and PI-103 in triple-negative breast cancer. ](https://pubmed.ncbi.nlm.nih.gov/25884663/) Jang NY, Kim DH, Cho BJ, Choi EJ, Lee JS, Wu HG, Chie EK, Kim IA.Jang NY, et al.BMC Cancer. 2015 Mar 3;15:89. doi: 10.1186/s12885-015-1090-7.BMC Cancer. 2015.PMID: 25884663Free PMC article. * [ Jab1 regulates HRR mRNA stability to modulate PARP inhibitor sensitivity in triple-negative breast cancer. ](https://pubmed.ncbi.nlm.nih.gov/40819058/) Peng X, Wang Y, Yu Z, Huang S, Zhang S, Zhong Z, Wang Y, Liu S, Wang K, Nicot C, Claret FX, Kong D.Peng X, et al.Mol Cancer. 2025 Aug 16;24(1):217. doi: 10.1186/s12943-025-02422-7.Mol Cancer. 2025.PMID: 40819058Free PMC article. * [ BUB1 regulates non-homologous end joining pathway to mediate radioresistance in triple-negative breast cancer. ](https://pubmed.ncbi.nlm.nih.gov/38863037/) Sriramulu S, Thoidingjam S, Chen WM, Hassan O, Siddiqui F, Brown SL, Movsas B, Green MD, Davis AJ, Speers C, Walker E, Nyati S.Sriramulu S, et al.J Exp Clin Cancer Res. 2024 Jun 11;43(1):163. doi: 10.1186/s13046-024-03086-9.J Exp Clin Cancer Res. 2024.PMID: 38863037Free PMC article. * [ AZD6738 overcomes acquired olaparib resistance in BRCA1 mutation triple-negative breast cancer through down-regulation of BRCA2 and RAD51. ](https://pubmed.ncbi.nlm.nih.gov/42120731/) Huang L, Yang Y, Dai L, Zhou J, Shao J, Qian B.Huang L, et al.Sci Rep. 2026 May 12;16(1):21707. doi: 10.1038/s41598-026-52778-z.Sci Rep. 2026.PMID: 42120731Free PMC article. * [ BRCA1 deficiency in triple-negative breast cancer: Protein stability as a basis for therapy. ](https://pubmed.ncbi.nlm.nih.gov/36493696/) Choi E, Mun GI, Lee J, Lee H, Cho J, Lee YS.Choi E, et al.Biomed Pharmacother. 2023 Feb;158:114090. doi: 10.1016/j.biopha.2022.114090. Epub 2022 Dec 6.Biomed Pharmacother. 2023.PMID: 36493696Review. 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