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

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.

MCM10 facilitates the invaded/migrated potentials of breast cancer cells via Wnt/β‐catenin signaling and is positively interlinked with poor prognosis in breast carcinoma

“…A similar trend for MCM10 has also been reported in cervical cancer, and overexpression of MCM10 is a stage‐specific marker, indicating that MCM10 is critical in the progression of cervical cancer . One mutually supportive report by Mahadevappa et al has suggested the role of MCM10 in breast cancer progression. Their findings and our research data jointly indicated that MCM10 is a potential prognostic marker and target for breast cancer therapy.…”

Transcriptional Expression of Minichromosome Maintenance 10 as an Independent Negative Predictor of Survival in Hepatocellular Carcinoma

“…Recent researches have unveiled that MCM10 plays a key functional role as a DNA binding scaffold for guarding against replication stress in replication, and is involved in maintaining genome integrity, indicating that its dysregulation may contribute to genomic instability, which can induce abnormal proliferation and cancer progression in turn [41,42] . Over-expression of MCM10 had been found in a variety of malignancies, such as prostate [19] , breast [20] , pancreatic [21] , lung [43] and cervical [44] cancers. In cancer cell lines, knockdown of MCM10 expression showed noticeably decreased tumor properties such as proliferation, migration and colony formation, but increased cell apoptosis [19,20] .…”

“…Over-expression of MCM10 had been found in a variety of malignancies, such as prostate [19] , breast [20] , pancreatic [21] , lung [43] and cervical [44] cancers. In cancer cell lines, knockdown of MCM10 expression showed noticeably decreased tumor properties such as proliferation, migration and colony formation, but increased cell apoptosis [19,20] . Several lines of evidence showed that MCM10 was of prognostic relevance for predicting survivals in malignant tumors [19][20][21] .…”

“…MCM10, along with CDC45-MCM2-7 complex, is a subtype of the MCM family relating to initiating DNA replication and regulating cell proliferation in late G1 or early S phase of cell cycle [16][17][18] . Accumulating studies have shown that MCM10 expression tended to be higher in a variety of malignancies [19][20][21][22][23] . Over-expression of MCM10 in some cancers had a close relationship with tumor progression and dismal clinical outcomes [19][20][21] .…”

“…Accumulating studies have shown that MCM10 expression tended to be higher in a variety of malignancies [19][20][21][22][23] . Over-expression of MCM10 in some cancers had a close relationship with tumor progression and dismal clinical outcomes [19][20][21] . Furthermore, MCM10 was identi ed as one of the top-ranking genes which is enriched in cancer-related pathways [24] .…”