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A novel somatic mutation of SIN3A detected in breast cancer by whole-exome sequencing enhances cell proliferation through ERα expression

Breast cancer is the most frequent tumor in women, and in nearly two-thirds of cases, the tumors express estrogen receptor α (ERα, encoded by ESR1). Here, we performed whole-exome sequencing of 16 breast cancer tissues classified according to ESR1 expression and 12 samples of whole blood, and detect...

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Autores principales: Watanabe, Kenji, Yamamoto, Shigeru, Sakaguti, Syuiti, Isayama, Keishiro, Oka, Masaaki, Nagano, Hiroaki, Mizukami, Yoichi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6207735/
https://www.ncbi.nlm.nih.gov/pubmed/30375428
http://dx.doi.org/10.1038/s41598-018-34290-1
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author Watanabe, Kenji
Yamamoto, Shigeru
Sakaguti, Syuiti
Isayama, Keishiro
Oka, Masaaki
Nagano, Hiroaki
Mizukami, Yoichi
author_facet Watanabe, Kenji
Yamamoto, Shigeru
Sakaguti, Syuiti
Isayama, Keishiro
Oka, Masaaki
Nagano, Hiroaki
Mizukami, Yoichi
author_sort Watanabe, Kenji
collection PubMed
description Breast cancer is the most frequent tumor in women, and in nearly two-thirds of cases, the tumors express estrogen receptor α (ERα, encoded by ESR1). Here, we performed whole-exome sequencing of 16 breast cancer tissues classified according to ESR1 expression and 12 samples of whole blood, and detected 310 somatic mutations in cancer tissues with high levels of ESR1 expression. Of the somatic mutations validated by a different deep sequencer, a novel nonsense somatic mutation, c.2830 C>T; p.Gln944*, in transcriptional regulator switch-independent 3 family member A (SIN3A) was detected in breast cancer of a patient. Part of the mutant protein localized in the cytoplasm in contrast to the nuclear localization of ERα, and induced a significant increase in ESR1 mRNA. The SIN3A mutation obviously enhanced MCF7 cell proliferation. In tissue sections from the breast cancer patient with the SIN3A c.2830 C>T mutation, cytoplasmic SIN3A localization was detected within the tumor regions where nuclear enlargement was observed. The reduction in SIN3A mRNA correlates with the recurrence of ER-positive breast cancers on Kaplan-Meier plots. These observations reveal that the SIN3A mutation has lost its transcriptional repression function due to its cytoplasmic localization, and that this repression may contribute to the progression of breast cancer.
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spelling pubmed-62077352018-11-01 A novel somatic mutation of SIN3A detected in breast cancer by whole-exome sequencing enhances cell proliferation through ERα expression Watanabe, Kenji Yamamoto, Shigeru Sakaguti, Syuiti Isayama, Keishiro Oka, Masaaki Nagano, Hiroaki Mizukami, Yoichi Sci Rep Article Breast cancer is the most frequent tumor in women, and in nearly two-thirds of cases, the tumors express estrogen receptor α (ERα, encoded by ESR1). Here, we performed whole-exome sequencing of 16 breast cancer tissues classified according to ESR1 expression and 12 samples of whole blood, and detected 310 somatic mutations in cancer tissues with high levels of ESR1 expression. Of the somatic mutations validated by a different deep sequencer, a novel nonsense somatic mutation, c.2830 C>T; p.Gln944*, in transcriptional regulator switch-independent 3 family member A (SIN3A) was detected in breast cancer of a patient. Part of the mutant protein localized in the cytoplasm in contrast to the nuclear localization of ERα, and induced a significant increase in ESR1 mRNA. The SIN3A mutation obviously enhanced MCF7 cell proliferation. In tissue sections from the breast cancer patient with the SIN3A c.2830 C>T mutation, cytoplasmic SIN3A localization was detected within the tumor regions where nuclear enlargement was observed. The reduction in SIN3A mRNA correlates with the recurrence of ER-positive breast cancers on Kaplan-Meier plots. These observations reveal that the SIN3A mutation has lost its transcriptional repression function due to its cytoplasmic localization, and that this repression may contribute to the progression of breast cancer. Nature Publishing Group UK 2018-10-30 /pmc/articles/PMC6207735/ /pubmed/30375428 http://dx.doi.org/10.1038/s41598-018-34290-1 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Watanabe, Kenji
Yamamoto, Shigeru
Sakaguti, Syuiti
Isayama, Keishiro
Oka, Masaaki
Nagano, Hiroaki
Mizukami, Yoichi
A novel somatic mutation of SIN3A detected in breast cancer by whole-exome sequencing enhances cell proliferation through ERα expression
title A novel somatic mutation of SIN3A detected in breast cancer by whole-exome sequencing enhances cell proliferation through ERα expression
title_full A novel somatic mutation of SIN3A detected in breast cancer by whole-exome sequencing enhances cell proliferation through ERα expression
title_fullStr A novel somatic mutation of SIN3A detected in breast cancer by whole-exome sequencing enhances cell proliferation through ERα expression
title_full_unstemmed A novel somatic mutation of SIN3A detected in breast cancer by whole-exome sequencing enhances cell proliferation through ERα expression
title_short A novel somatic mutation of SIN3A detected in breast cancer by whole-exome sequencing enhances cell proliferation through ERα expression
title_sort novel somatic mutation of sin3a detected in breast cancer by whole-exome sequencing enhances cell proliferation through erα expression
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6207735/
https://www.ncbi.nlm.nih.gov/pubmed/30375428
http://dx.doi.org/10.1038/s41598-018-34290-1
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