Tumor Biology

, Volume 35, Issue 8, pp 8289–8299 | Cite as

Revisiting the role of MCL1 in tumorigenesis of solid cancer: gene expression correlates with antiproliferative phenotype in breast cancer cells and its functional regulatory variants are associated with reduced cancer susceptibility

  • Sheng Wang
  • Yan Jiang
  • Jin Liu
  • Yuanyuan Zhao
  • Chan Xiang
  • Rong Ma
  • Haidong Gao
  • Li Jin
  • Fuchu He
  • Haijian Wang
Research Article

Abstract

Compared to the well-defined anti-apoptotic role of myeloid cell leukemia sequence 1 (MCL1), its antiproliferative function in tumorigenesis is less studied. We had recently reported that regulatory variants of MCL1 contribute to enhanced promoter activity but reduced risk of lung cancer. We hypothesized that MCL1 expression may manifest antiproliferative phenotype and its functional variations may have etiological relevance for breast cancer. We manipulated MCL1 expression in MCF-7 cells and MDA231 with overexpression and knockdown, analyzed the effects on cell viability and cell cycling phase, and characterized the correlation with expression profiles of key regulators of cell cycle. We further genotyped the −190 insertion polymorphism and the neighboring single nucleotide polymorphisms (SNPs) in 745 breast cancer patients and 537 controls and analyzed their association with cancer risk. We confirmed that heightened expression of MCL1 resulted in decreased proliferation ability of breast cancer cells. We further observed that MCL1 overexpression in breast cancer cells resulted in cell cycle progression arresting in S phase and concomitant enhanced expression of p27, which could be rescued by p27 knockdown with co-transfection of small interfering RNA (siRNA). Furthermore, we found a significant reduction in breast cancer risk [odds ratio (OR) = 0.74; 95 % confidence interval (CI) = 0.59–0.93] associated with −190 insertion genotype; the expression-enhancing regulatory haplotype (OR 0.79; 95 % CI 0.66–0.95) and diplotype (OR 0.71; 95 % CI 0.57–0.89) were consistently associated with decreased cancer susceptibility. The study demonstrates that the expression-enhancing regulatory variants of MCL1 are protective modifiers of breast cancer risk, and reduced cell proliferation and arrested cell cycle progression partly mediated by p27 might be the underlying mechanism.

Keywords

MCL1 Regulatory polymorphism Breast cancer Case-control study Antiproliferation Cell cycle 

Notes

Acknowledgments

This study was supported by grants from the National Natural Science Foundation of China (81172093 and 81372526), Shanghai Rising-Star Program (12QH1400200), and Shanghai Pujiang Program (11PJD005).

Conflicts of interest

None.

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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Sheng Wang
    • 1
  • Yan Jiang
    • 1
    • 2
  • Jin Liu
    • 2
  • Yuanyuan Zhao
    • 1
  • Chan Xiang
    • 1
  • Rong Ma
    • 3
  • Haidong Gao
    • 3
  • Li Jin
    • 1
  • Fuchu He
    • 1
    • 2
    • 4
  • Haijian Wang
    • 1
  1. 1.State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences and Institutes of Biomedical SciencesFudan UniversityShanghaiChina
  2. 2.Department of ChemistryFudan UniversityShanghaiChina
  3. 3.Department of Breast SurgeryQilu Hospital of Shandong UniversityJinanChina
  4. 4.State Key Laboratory of Proteomics, Beijing Proteome Research CenterBeijing Institute of Radiation MedicineBeijingChina

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