ArticleCancer research2016
HER2 Signaling Drives DNA Anabolism and Proliferation through SRC-3 Phosphorylation and E2F1-Regulated Genes.
Article in Cancer research, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
30 citing papers in PubMed, 1 synthesis or guideline pooled it, 49 citations in OpenAlex.
- Intercepting Premalignant, Preinvasive Breast Lesions Through Vaccination.Frontiers in immunology · 2021Pooled it
- Next Frontier in HER2+/HR+ Breast Cancer: Leveraging Cell Cycle Control with CDK4/6 Inhibitors.Journal of personalized medicine · 2026Review
- Metabolic Vulnerabilities as a Therapeutic Target in Breast Cancer.Current oncology (Toronto, Ont.) · 2026Review
- Cyclin-Dependent 4/6 Kinase Inhibitors for Treatment of HER2-Positive Breast Cancer: 2026 Update.Cancers · 2026Review
- Adaptive Proteomic Changes in Protein Metabolism and Mitochondrial Alterations Associated with Resistance to Trastuzumab and Pertuzumab Therapy in HER2-Positive Breast Cancer.International journal of molecular sciences · 2025Article
- Inhibition of METTL14 overcomes CDK4/6 inhibitor resistance driven by METTL14-m6A-E2F1-axis in ERα-positive breast cancer.Journal of nanobiotechnology · 2025Article
- Real-World Efficacy of HLX02-Based Neoadjuvant Therapy in HER2-Positive Breast Cancer: Clinical Insights and Future Directions.The breast journal · 2025Article
- CDK4/6 Inhibitor Resistance in ER+ Breast Cancer.Advances in experimental medicine and biology · 2025Review
- E2F1-Associated Purine Synthesis Pathway Is a Major Component of the MET-DNA Damage Response Network.Cancer research communications · 2024Article
- Lead Compound Development of SRC-3 Inhibitors with Improved Pharmacokinetic Properties and Anticancer Efficacy.Journal of medicinal chemistry · 2024Article
- Metabolic heterogeneity affects trastuzumab response and survival in HER2-positive advanced gastric cancer.British journal of cancer · 2024Observational
- Bibliometric analysis and visualization of endocrine therapy for breast cancer research in the last two decade.Frontiers in endocrinology · 2023Article
- Clinical considerations of CDK4/6 inhibitors in HER2 positive breast cancer.Frontiers in oncology · 2023Review
- Multiplexed and reproducible high content screening of live and fixed cells using Dye Drop.Nature communications · 2022Article
- Targeting Cell Cycle Progression in HER2+ Breast Cancer: An Emerging Treatment Opportunity.International journal of molecular sciences · 2022Review
- HER2-PI9 and HER2-I12: two novel and functionally active splice variants of the oncogene HER2 in breast cancer.Journal of cancer research and clinical oncology · 2021Article
- Metabolomic therapy response prediction in pretherapeutic tissue biopsies for trastuzumab in patients with HER2-positive advanced gastric cancer.Clinical and translational medicine · 2021Article
- SRC-3, a Steroid Receptor Coactivator: Implication in Cancer.International journal of molecular sciences · 2021Review
- Steroid receptor coactivator 3 (SRC-3/AIB1) is enriched and functional in mouse and human Tregs.Scientific reports · 2021Article
- An evaluation of palbociclib as a breast cancer treatment option: a current update.Expert opinion on pharmacotherapy · 2021Article
Corrections and comments
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Authors and funding
11 authors at 1 institution in 1 country.
Funding
Abstract
Approximately 20% of early-stage breast cancers display amplification or overexpression of the ErbB2/HER2 oncogene, conferring poor prognosis and resistance to endocrine therapy. Targeting HER2(+) tumors with trastuzumab or the receptor tyrosine kinase (RTK) inhibitor lapatinib significantly improves survival, yet tumor resistance and progression of metastatic disease still develop over time. Although the mechanisms of cytosolic HER2 signaling are well studied, nuclear signaling components and gene regulatory networks that bestow therapeutic resistance and limitless proliferative potential are incompletely understood. Here, we use biochemical and bioinformatic approaches to identify effectors and targets of HER2 transcriptional signaling in human breast cancer. Phosphorylation and activity of the Steroid Receptor Coactivator-3 (SRC-3) is reduced upon HER2 inhibition, and recruitment of SRC-3 to regulatory elements of endogenous genes is impaired. Transcripts regulated by HER2 signaling are highly enriched with E2F1 binding sites and define a gene signature associated with proliferative breast tumor subtypes, cell-cycle progression, and DNA replication. We show that HER2 signaling promotes breast cancer cell proliferation through regulation of E2F1-driven DNA metabolism and replication genes together with phosphorylation and activity of the transcriptional coactivator SRC-3. Furthermore, our analyses identified a cyclin-dependent kinase (CDK) signaling node that, when targeted using the CDK4/6 inhibitor palbociclib, defines overlap and divergence of adjuvant pharmacologic targeting. Importantly, lapatinib and palbociclib strictly block de novo synthesis of DNA, mostly through disruption of E2F1 and its target genes. These results have implications for rational discovery of pharmacologic combinations in preclinical models of adjuvant treatment and therapeutic resistance.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.