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Enhanced cancer cell proliferation and aggressive phenotype counterbalance in breast cancer with high BRCA1 gene expression

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Abstract

Purpose

While comprehensive research exists on the mutation of the DNA repair gene BRCA1, limited information is available regarding the clinical significance of BRCA1 gene expression. Given that cancer cell proliferation is aggrevated by DNA repair, we hypothesized that high BRCA1 gene expression breast cancer (BC) might be linked with aggressive tumor biology and poor clinical outcomes.

Methods

The cohorts: The Cancer Genome Atlas (TCGA, n = 1069), METABRIC (n = 1903), and SCAN-B (n = 3273) were utilzed to obtain data of 6245 BC patients.

Results

BC patients without BRCA1 mutation exhibited higher BRCA1 expression, which was associated with DNA repair functionality. However, no such correlation was observed with BRCA2 expression. The association of high BRCA1 expression with cancer cell proliferation was evidenced by significant enrichment of cell proliferation-related gene sets, higher histological grade, and proliferation score. Furthermore, increased levels of homologous recombination deficiency, intratumoral heterogeneity, and altered fractions were associated with high BRCA1 expression. Moreover, BC with high BRCA1 expression exhibited reduced infiltration of dendritic cells and CD8 T-cells, while showing increased infiltration of Th1 cells. Surprisingly, BRCA1 expression was not associated with the survival of BC irrespective of the subtypes. Conversely, BC with low BRCA1 expression enriched cancer aggravating pathway gene sets, such as Cancer Stem Cell-related signaling (NOTCH and HEDGEHOG), Angiogenesis, Epithelial-Mesenchymal Transition, Inflammatory Response, and TGF-beta signaling.

Conclusion

Despite being linked to heightened proliferation of cancer cells and unassertive phenotype, BRCA1 expression did not show any association with survival in BC.

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Data availability

No datasets were generated or analysed during the current study.

Abbreviations

SCAN-B:

The Sweden Cancerome Analysis Network—Breast

METABRIC:

Molecular Taxonomy of Breast Cancer International Consortium

TCGA:

The Cancer Genome Atlas

GEO:

Gene Expression Omnibus

GSEA:

Gene Set Enrichment Analysis

IRB:

Institutional review board

NES:

Normalized enrichment score

FDR:

False discovery rate

CYT:

Cytolytic activity score

MKI67:

Ki67 gene expression

TNBC:

Triple-negative breast cancer

TME:

Tumor microenvironment

mv:

Microvascular

ly:

Lymphatic

HRD:

Homologous recombination deficiency

SNV:

Single-nucleotide variant

TIME:

Tumor immune microenvironment

Th1:

T helper type 1 T-cell

Th2:

T helper type 2 T-cell

DC:

Dendritic cell

Treg:

Regulatory T-cell

Tgd:

Gamma delta T-cell

M1:

Type 1 macrophages

M2:

Type 2 macrophages

EMT:

Epithelial-Mesenchymal Transition

CSC:

Cancer stem cell

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Acknowledgements

This research was supported by Rotary Club District 2830 to K. C., K. T. was supported by US National Institutes of Health grants R37CA248018, R01CA-250412, R01CA251545, R01EB029596, as well as US Department of Defense BCRP grants W81XWH-19-1-0674 and W81XWH-19-1-0111.

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Author notes

  1. Kohei Chida and Masanori Oshi contributed equally to this work.

Authors and Affiliations

  1. Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Elm & Carlton Streets, Buffalo, NY, 14263, USA

    Kohei Chida, Masanori Oshi, Takumi Sato, Maya Penelope Takabe & Kazuaki Takabe

  2. Department of Gastroenterological Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, 036-8562, Japan

    Kohei Chida & Kenichi Hakamada

  3. Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, 236-0004, Japan

    Masanori Oshi, Itaru Endo & Kazuaki Takabe

  4. Department of Hematology and Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA

    Arya Mariam Roy

  5. Department of Medical Science, The University of Tokyo, Tokyo, 113-8654, Japan

    Takumi Sato

  6. Department of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA

    Li Yan

  7. Department of Surgery, School of Medicine and Biomedical Sciences, University at Buffalo Jacobs, The State University of New York, Buffalo, NY, 14263, USA

    Kazuaki Takabe

  8. Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo, 160-8402, Japan

    Kazuaki Takabe

  9. Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, 951-8510, Japan

    Kazuaki Takabe

  10. Department of Breast Surgery, Fukushima Medical University School of Medicine, Fukushima, 960-1295, Japan

    Kazuaki Takabe

  11. Department of Breast Surgery, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA

    Kazuaki Takabe

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  1. Kohei Chida
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Masanori Oshi and Li Yan. The first draft of the manuscript was written by Kohei Chida, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Kazuaki Takabe.

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Chida, K., Oshi, M., Roy, A.M. et al. Enhanced cancer cell proliferation and aggressive phenotype counterbalance in breast cancer with high BRCA1 gene expression. Breast Cancer Res Treat (2024). https://doi.org/10.1007/s10549-024-07421-8

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