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

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.

Loss of Neuroligin 4X Induces An Intrinsic Innate Immune Response in TNBC

“…Our previous the first study to link the expression of neuronal cell adhesion molecules, neuroligins, in breast cancer [18]. NLGN4X plays a vital role in enhancing tumorigenesis and aggressiveness of breast cancer with MCPH1 loss/mutation [35]. Here we describe for the first time that loss of NLGN4X activates MAVS-IRF signaling that induces IFN signaling and cytokine secretion from TNBC.…”

Identification of Breast Cancer Subtype-Specific Biomarkers by Integrating Copy Number Alterations and Gene Expression Profiles

“…These data therefore suggested that this gene is involved in the development of BC, despite its role needing to be further analyzed. In addition, mutated MCPH1 down-regulates histone genes and leads to migration and invasion of the cells [ 32 ]. Frequent deletions and methylation of MCPH1 were reported in many cancers, including BC, and were also associated with tumor stages in BC [ 33 ].…”

Cancer‐associated mutations in the condensin II subunit CAPH2 cause genomic instability through telomere dysfunction and anaphase chromosome bridges

“…is a tumor suppressor that is downregulated in multiple cancer types (Tervasmaki et al, 2019;Venkatesh et al, 2013;Wang et al, 2014).…”

“…It has been suggested through previous work that condensin II functions alone or with other chromatin binding factors to prevent cancer progression. Two factors important for modulating the binding of condensin II to chromatin are the tumor suppressors Rb (Longworth et al, 2008) and MCPH1 (Tervasmaki et al, 2019; Trimborn et al, 2006; Venkatesh et al, 2013; Wang et al, 2014; Yamashita et al, 2011). Rb binds to CAPD3, and Rb is required for proper loading of condensin II onto chromatin (Longworth et al, 2008).…”