University of Oulu

Tervasmäki, A. , Mantere, T. , Eshraghi, L. , Laurila, N. , Tuppurainen, H. , Ronkainen, V. , Koivuluoma, S. , Devarajan, R. , Peltoketo, H. and Pylkäs, K. (2019), Tumor suppressor MCPH1 regulates gene expression profiles related to malignant conversion and chromosomal assembly. Int. J. Cancer, 145: 2070-2081. doi:10.1002/ijc.32234

Tumor suppressor MCPH1 regulates gene expression profiles related to malignant conversion and chromosomal assembly

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Author: Tervasmäki, Anna1; Mantere, Tuomo1; Eshraghi, Leila1;
Organizations: 1Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit and Biocenter Oulu, University of Oulu, Oulu, Finland
2Biocenter Oulu, Light Microscopy Core Facility, University of Oulu, Oulu, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 10.6 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe2019093030494
Language: English
Published: John Wiley & Sons, 2019
Publish Date: 2019-09-30
Description:

Abstract

Strong inherited predisposition to breast cancer is estimated to cause about 5–10% of all breast cancer cases. As the known susceptibility genes, such as BRCA1 and BRCA2, explain only a fraction of this, additional predisposing genes and related biological mechanisms are actively being searched for. We have recently identified a recurrent MCPH1 germline mutation, p.Arg304ValfsTer3, as a breast cancer susceptibility allele. MCPH1 encodes a multifunctional protein involved in maintenance of genomic integrity and it is also somatically altered in various cancer types, including breast cancer. Additionally, biallelic MCPH1 mutations are causative for microcephaly and at cellular level premature chromosome condensation. To study the molecular mechanisms leading to cancer predisposition and malignant conversion, here we have modeled the effect of MCPH1 p.Arg304ValfsTer3 mutation using gene‐edited MCF10A breast epithelial cells. As a complementary approach, we also sought for additional potential cancer driver mutations in MCPH1 p.Arg304ValfsTer3 carrier breast tumors. We show that mutated MCPH1 de‐regulates transcriptional programs related to invasion and metastasis and leads to downregulation of histone genes. These global transcriptional changes are mirrored by significantly increased migration and invasion potential of the cells as well as abnormal chromosomal condensation both before and after mitosis. These findings provide novel molecular insights to MCPH1 tumor suppressor functions and establish a role in regulation of transcriptional programs related to malignant conversion and chromosomal assembly. The MCPH1 p.Arg304ValfsTer3 carrier breast tumors showed recurrent tumor suppressor gene TP53 mutations, which were also significantly over‐represented in breast tumors with somatically inactivated MCPH1.

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Series: International journal of cancer
ISSN: 0020-7136
ISSN-E: 1097-0215
ISSN-L: 0020-7136
Volume: 145
Issue: 8
Pages: 2070 - 2081
DOI: 10.1002/ijc.32234
OADOI: https://oadoi.org/10.1002/ijc.32234
Type of Publication: A1 Journal article – refereed
Field of Science: 3122 Cancers
3111 Biomedicine
Subjects:
Funding: Ida Montin’s foundation; K. Albin Johansson’s foundation; Oulu University Hospital; Terveyden Tutkimuksen Toimikunta 307808, 314183; The Cancer Foundation of Finland sr; the Sigrid Juselius Foundation; University of Oulu.
Copyright information: © 2019 The Authors.International Journal of Cancerpublished by John Wiley & Sons Ltd on behalfof UICC. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distributionand reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
  https://creativecommons.org/licenses/by-nc/4.0/