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The SWI/SNF subunit SMARCD3 regulates cell cycle progression and predicts survival outcome in ER+ breast cancer

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Abstract

Purpose

Chromatin remodeling plays an essential role in regulating transcriptional networks and timing of gene expression. Chromatin remodelers such as SWItch/Sucrose Non-Fermentable (SWI/SNF) harbor many protein components, with the catalytic subunit providing ATPase activity to displace histones along or from the DNA molecules, and associated subunits ensuring tissue specificity and transcriptional or co-transcriptional activities. Mutations in several of the SWI/SNF subunits have been linked to cancer. Here, we investigate between SMARCD3/Baf60c expression and hormone-positive (ER+) breast cancer.

Methods

 The level of SMARCD3 was detected by immunohistochemistry in breast cancer patient samples, and expression levels of SMARCD1, SMARCD2, and SMARCD3 were investigated using publicly available datasets from large cohorts of breast cancer patients. Using molecular biology and microscopy, we interrogated the cellular consequences of lower SMARCD3 expression.

Results

 Lower proliferation rates were observed in SMARCD3-depleted cells, which reflects a failure of the cell cycle progression and an increase in endoreplication. In the absence of SMARCD3, p21 accumulates in cells, but does not halt the cell cycle, and DNA damage accumulates and remains unrepaired.

Conclusion

 Taken together, our data begin to explain why ER+ breast cancer patients with low-SMARCD3 expressing tumors exhibit reduced survival rates compared to patients expressing normal or higher levels of SMARCD3. SMARCD3 might act as a tumor suppressor through regulation of cell cycle checkpoints and could be a reliable and specific breast cancer prognostic biomarker.

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Funding

ED and PHGD are recipient of National Breast Cancer Fellowships. RT and BDLP are recipient of the Princess Alexandra Research Foundation. CS and MG are supported by funding from Mater Foundation. This work was funded by ECR13-04 (NBCF) and Cancer Council Queensland (CCQ). The Mays cancer center is supported by a NCI Cancer Center Support Core Grant P30 CA054174.

Author information

Author notes

  1. Bárbara de la Peña Avalos

    Present address: Department of Biochemistry and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

Authors and Affiliations

  1. IHBI, Queensland University of Technology, Brisbane, QLD, Australia

    Romain Tropée, Bárbara de la Peña Avalos, Pascal H. G. Duijf & Eloïse Dray

  2. Department of Biochemistry and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

    Eloïse Dray

  3. Cancer Pathology Research Group, Mater Research Institute, The University of Queensland, Translational Research Institute, 37 Kent St, Woolloongabba, QLD, 4102, Australia

    Madeline Gough, Cameron Snell & Eloïse Dray

  4. Mater Pathology, Mater Hospital Brisbane, Mater Misericordiae Limited, South Brisbane, QLD, 4101, Australia

    Madeline Gough & Cameron Snell

  5. University of Queensland Diamantina Institute, The University of Queensland, Brisbane, QLD, Australia

    Pascal H. G. Duijf

  6. Mays Cancer Center, UT Health San Antonio MD Anderson, San Antonio, TX, USA

    Bárbara de la Peña Avalos & Eloïse Dray

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  1. Romain Tropée
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Contributions

ED, RT, and PHGD designed research, RT, BDLP, MG. and CS performed research, RT and PHGD. Wrote analysis pipelines, RT, ED, PHGD and CS analyzed data; and ED, PHGD and RT wrote the paper.

Corresponding author

Correspondence to Eloïse Dray.

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The authors declare no conflict of interest.

Ethical approval

All procedures performed in studies involving human samples were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Research involving human and animal participants

This article does not contain any studies with human participants or animals performed by any of the authors. Samples acquired from US Biomax guarantees informed consent was obtained from all individual participants included in the study. Subsequent staining experimental protocols were approved by the QUT ethics committee. Samples included in the Mater TMA were cleared for use by the Mater hospital ethics committee.

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Tropée, R., de la Peña Avalos, B., Gough, M. et al. The SWI/SNF subunit SMARCD3 regulates cell cycle progression and predicts survival outcome in ER+ breast cancer. Breast Cancer Res Treat 185, 601–614 (2021). https://doi.org/10.1007/s10549-020-05997-5

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  • DOI: https://doi.org/10.1007/s10549-020-05997-5

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