Int J Biol Sci 2022; 18(9):3827-3844. doi:10.7150/ijbs.69344 This issue

Research Paper

Over-Activation of Minichromosome Maintenance Protein 10 Promotes Genomic Instability in Early Stages of Breast Cancer

Muhammad Jameel Mughal1*, Kin Iong Chan2*, Ravikiran Mahadevappa1, Sin Wa Wong1, Kit Cheng Wai2, Hang Fai Kwok1✉

1. Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida de Universidade, Taipa, Macau SAR; MoE Frontiers Science Center for Precision Oncology, University of Macau, Avenida de Universidade, Taipa, Macau SAR
2. Centre for Precision Medicine Research and Training, Faculty of Health Sciences, University of Macau, Avenida de Universidade, Taipa, Macau SAR; Department of Pathology, Kiang Wu Hospital, Macau SAR
*Co-first author

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Citation:
Mughal MJ, Chan KI, Mahadevappa R, Wong SW, Wai KC, Kwok HF. Over-Activation of Minichromosome Maintenance Protein 10 Promotes Genomic Instability in Early Stages of Breast Cancer. Int J Biol Sci 2022; 18(9):3827-3844. doi:10.7150/ijbs.69344. Available from https://www.ijbs.com/v18p3827.htm

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Abstract

Graphic abstract

Genomic instability is considered as one of the key hallmark during cancer development and progression. Cellular mechanisms, such as DNA replication initiation, DNA damage and repair response, apoptosis etc are observed to block progression of genomic instability and thereby induce protective effects against cancer. DNA replication initiation protein MCM10 has been previously observed to have an increased expression in different cancer subtypes. However, MCM10 association with genomic instability, cancer development and its relevant mechanisms remain unknown. Here, using a breast cancer model, we observe a significant association of MCM10 with the degree of clinical aggressiveness in breast cancer patients. By overexpression of MCM10, we observed that MCM10 promotes tumorigenic properties in immortal non-tumorigenic mammary cells by increasing proliferation, shortening the cell cycle, and promoting tumorigenic characters in in-vivo mimicking conditions. Furthermore, overexpression of MCM10 is found to induce accumulation of ssDNA followed by overexpression of ssDNA binding protein RPA2. Mesenchymal markers such as up-regulation of Vimentin, transcription factor Snail and Twist2, and the down-regulation of E-cadherin were observed in MCM10 overexpression cells. Overall, the findings of this study revealed a novel mechanism by which MCM10 promotes genomic instability and breast cancer progression, and effectively differentiates the active degree of breast cancer aggressiveness. Thus, MCM10 has the potential to be a clinically useful biomarker as well as a therapeutic target for future breast cancer treatment.

Keywords: MCM10, DNA replication, DNA damage response, genomic instability, breast cancer