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Decoding BRCA1 promoter hypermethylation: a new frontier in understanding sporadic breast cancer

Cancer Gene Therapy volume 32, pages 1400–1413 (2025)Cite this article

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Abstract

The role of epimutations in sporadic oncogenesis has been a hot topic of debate and speculation, as hereditary mutations account for merely 5–10% of cancers. One such epimutation, BRCA1 promoter hypermethylation (BPM), is associated with BRCA1 inactivation at variable frequencies in sporadic breast cancers. Unlike hereditary BRCA1 mutations, the role of BPM in tumorigenesis remains obscure. To investigate this, we employed a modified CRISPR approach to induce site-specific methylations in the wild-type BRCA1 promoter, mimicking BPM under clinical conditions. Our research revealed complex pathways influenced by BPM that accelerate tumor formation and progression. We found that BPM downregulates BRCA1 by modulating ER-α expression, thus affecting the balance between BRCA1 isoforms β and α. BPM also regulates the lncRNA NBR2, which shares the BRCA1 promoter region. Remarkably, silencing NBR2 initiates a feedback loop that exacerbates BRCA1 downregulation and supports tumorigenesis. Shortly after BPM induction, tumor proliferation is enhanced by increased β-hCG and ER-α expression, alongside decreased PR levels. However, prolonged BPM maintenance leads to the remodulation of hormone receptors, resulting in a hormone receptor-negative status. Finally, we demonstrate the higher growth potential and invasiveness of BPM tumors through novel hypermethylation-based xenograft models. Comparative proteomic analysis of BPM cells at two different timepoints post-methylation induction identified diagnostic and prognostic markers. Key molecular biomarkers, including NBR2, β-hCG, ER-α, and associated proteins such as HSP90, STAT1, SPEN, and TFF1, have been identified as potential therapeutic targets for BRCA1-defective breast cancers.

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Fig. 1: Generation of stable BPM leads to downregulation of BRCA1.
Fig. 2: BPM leads to BRCA1 downregulation via modulation of BRCA1 transcriptional isoforms.
Fig. 3: BPM leads to NBR2 downregulation, activating a feedback loop and causes β-hCG induction.
Fig. 4: BPM modulates hormone receptors to support both cell proliferation and transformation to hormone receptor negative phenotype.
Fig. 5: Comparative proteomic analysis reveals key differences between methylation timelines.
Fig. 6: ER-α controls the regulation of alternate BRCA1 transcripts in BPM and knockdown cells.
Fig. 7: Xenograft tumors from BPM-induced cells demonstrate higher growth and invasiveness.

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Data availability

All Proteomics data and details of shRNAs and sgRNAs, plasmids, and generated cell lines in this experiment are included in this published article [and its supplementary information files].

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Acknowledgements

This study was funded by CSIR [Sanction Order No 37WS (0059)/2023-24/EMR-II/ASPIRE], University Grants Commission (UGC) India [482/OBC (CSIR UGC NET DEC. 2016)], DBT [00461], CSIR [09/716(0162)/2015-EMR-I], DST-SERB [DST-INSPIRE/03/2014/000159], UGC [958/(CSIR UGC NET DEC. 2016)], and DST-SERB [PDF/2015/00467]. We thank the Bio-imaging facility, Genomics facility, Animal Research facility, and Mass Spectrometry and Proteomics Core facility of Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, for their help and support in carrying out the experiments.

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Authors and Affiliations

  1. Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India

    Dipyaman Patra, Geetu Rose Varghese, Vishnu Sunil Jaikumar, Arathi Rajan, Neethu Krishnan, Krithiga Kuppuswamy, Rateeshkumar Thankappan & Priya Srinivas

  2. Department of Immunology, UPMC Hilman Cancer Centre, University of Pittsburgh, Pittsburgh, PA, USA

    Dipyaman Patra

  3. Department of General Virology, Institute of Advanced Virology, Thiruvananthapuram, Kerala, India

    Geetu Rose Varghese & Arathi Rajan

  4. University of South Australia, Adelaide, SA, Australia

    Vishnu Sunil Jaikumar

  5. Bioscience Research and Training Centre, Thonnakkal, Thiruvananthapuram, Kerala, India

    Krithiga Kuppuswamy

  6. Department of Molecular Biology and Genetics, DDRC Agilus Diagnostics, Ernakulam, Kerala, India

    Rateeshkumar Thankappan

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  1. Dipyaman Patra
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Contributions

DP—Writing—conceptualization, investigation, formal analysis, data curation, original draft, software. GRV—Formal analysis. VSJ—In vitro xenograft experiments. AR—DNA damage repair assays, data analysis. NK—Results interpretation. KK—Tissue pathology examination. RKT—CRISPR studies conceptualization based. PS—Conceptualization, supervision, resources, project administration, review, and editing.

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Correspondence to Priya Srinivas.

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All animal experiments were performed with the approval and according to the guidelines of Institutional Animal Ethics Committee (IAEC) (Protocol No. IAEC/807/PRY/2020). All in vitro experiments were performed with approval and according to the guidelines of Institutional Biosafety Committee (IBSC), RGCB.

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Patra, D., Varghese, G.R., Jaikumar, V.S. et al. Decoding BRCA1 promoter hypermethylation: a new frontier in understanding sporadic breast cancer. Cancer Gene Ther 32, 1400–1413 (2025). https://doi.org/10.1038/s41417-025-00969-7

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