Romain Tropée1, Bárbara de la Peña Avalos1,2,3, Madeline Gough4,5, Cameron Snell4,5, Pascal H G Duijf1,6, Eloïse Dray7,8,9,10. 1. IHBI, Queensland University of Technology, Brisbane, QLD, Australia. 2. Department of Biochemistry and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA. 3. Mays Cancer Center, UT Health San Antonio MD Anderson, San Antonio, TX, USA. 4. Cancer Pathology Research Group, Mater Research Institute, The University of Queensland, Translational Research Institute, 37 Kent St, Woolloongabba, QLD, 4102, Australia. 5. Mater Pathology, Mater Hospital Brisbane, Mater Misericordiae Limited, South Brisbane, QLD, 4101, Australia. 6. University of Queensland Diamantina Institute, The University of Queensland, Brisbane, QLD, Australia. 7. IHBI, Queensland University of Technology, Brisbane, QLD, Australia. dray@uthscsa.edu. 8. Department of Biochemistry and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA. dray@uthscsa.edu. 9. Cancer Pathology Research Group, Mater Research Institute, The University of Queensland, Translational Research Institute, 37 Kent St, Woolloongabba, QLD, 4102, Australia. dray@uthscsa.edu. 10. Mays Cancer Center, UT Health San Antonio MD Anderson, San Antonio, TX, USA. dray@uthscsa.edu.
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.
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.
Entities:
Keywords:
Breast cancer; Cell cycle; DNA damage repair; SMARCD3
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