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
- 206 Downloads
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.
KeywordsMCL1 Regulatory polymorphism Breast cancer Case-control study Antiproliferation Cell cycle
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
- 6.Krajewski S, Bodrug S, Krajewska M, Shabaik A, Gascoyne R, Berean K, et al. Immunohistochemical analysis of Mcl-1 protein in human tissues. Differential regulation of Mcl-1 and Bcl-2 protein production suggests a unique role for Mcl-1 in control of programmed cell death in vivo. Am J Pathol. 1995;146:1309–19.PubMedCentralPubMedGoogle Scholar
- 21.Jiang Y, Wang W, Wang J, Lu Y, Chen Y, Jin L, et al. Functional regulatory variants of MCL1 contribute to enhanced promoter activity and reduced risk of lung cancer in nonsmokers: implications for context-dependent phenotype of an antiapoptotic and antiproliferative gene in solid tumor. Cancer. 2012;118:2085–95.PubMedCrossRefGoogle Scholar
- 37.Hsiung CA, Lan Q, Hong YC, Chen CJ, Hosgood HD, Chang IS, et al. The 5p15.33 locus is associated with risk of lung adenocarcinoma in never-smoking females in Asia. PLoS Genet. 2010;6.Google Scholar