DNA Replication Licensing Protein MCM10 Promotes Tumor Progression and Is a Novel Prognostic Biomarker and Potential Therapeutic Target in Breast Cancer.

Ravikiran Mahadevappa,Shu-Dong Zhang,Hiu-Fung Yuen,Youzhi Zhu,Yao Lin,Shun Yuen,Henrique Neves,Hang Kwok,Yuchen Bai,Muhammad Jameel

doi:10.3390/cancers10090282

Abstract

Breast cancer is one of the most common malignancies in women worldwide. In breast cancer, the cell proliferation rate is known to influence the cancer malignancy. Recent studies have shown that DNA replication initiation/licensing factors are involved in cancer cell proliferation as well as cancer cell migration and invasion. Licensing factors have also been reported as important prognostic markers in lung, prostrate, and bladder cancers. Here, we studied the role of MCM10, a novel licensing factor, in breast cancer progression. From the public database, NCBI, we investigated six independent breast cancer patient cohorts, totaling 1283 patients. We observed a significant association between high MCM10 mRNA expression with tumor grading and patients’ survival time. Most importantly, using breast cancer cohorts with available treatment information, we also demonstrated that a high level of MCM10 is associated with a better response to conventional treatment. Similarly, in in vitro studies, the expression level of MCM10 in breast cancer cell lines is significantly higher compared to paired normal breast epithelium cells. Knockdown of MCM10 expression in the cancer cell line showed significantly decreased tumorigenic properties such as cell proliferation, migration and anchorage independence. The MCF7 breast cancer cell line, after MCM10 expression knockdown, showed significantly decreased tumorigenic properties such as cell proliferation, migration, and anchorage independent growth. Mechanistically, MCM10 expression is observed to be regulated by an Estrogen Receptor (ER) signaling pathway, where its expression is suppressed by the inhibition of the ER or serum withdrawal. Our results suggest that MCM10 plays an important role in breast cancer progression and is a potential prognostic/predictive biomarker and therapeutic target for breast cancer patients.

Highlights

Breast cancer is the second major cause of cancer related mortality in women, after lung cancer, worldwide [1]
Since the observations were consistent among all six independent breast cancer patient datasets, our results strongly suggest that MCM10 alone could be a prognostic marker for breast cancer patients
We further studied the expression of MCM10 in breast cancer cell lines

Summary

Introduction

Breast cancer is the second major cause of cancer related mortality in women, after lung cancer, worldwide [1]. Along with others, have previously observed the high expression of CDC6, CDT1 and MCM2-7 proteins in breast cancer progression [2,3,4]. Alterations in the expression profiles of the licensing proteins have been linked to various aspects of cancer [5,6]. Such as cancer cell proliferation [7,8] and cancer invasion [9]. High expression of CDC6, CDT1 and MCM family proteins may initiate replication at multiple regions on the DNA, thereby facilitating cancer cell proliferation. Reduction of MCM proteins in cancer cells is known to induce sensitivity to drugs such as aphidicolin, camptothecin, hydroxyurea, etc., and thereby promote an anti-proliferative effect [11,12]

Methods

Results

Conclusion