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

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.

MCL1 binding to the reverse BH3 motif of P18INK4C couples cell survival to cell proliferation

“…We confirmed this hypothesis using both cell growth studies and the Cell-Trace™ Violet dye dilution assay. This observation synergizes with prior studies that have highlighted the role of MCL1 in regulating apoptosis during the cell cycle, especially during mitosis 51,53,[57][58][59] . Our results suggest that having a sufficient amount of free MCL1, indicative of a non-apoptotic state, can promote cell growth and may aid in insuring that there is sufficient MCL1 to enable exit from mitosis once the cell cycle is complete.…”

Clinical outcomes of EGFR-TKI treatment and genetic heterogeneity in lung adenocarcinoma patients with EGFR mutations on exons 19 and 21

“…MCL1 gene expression was thought to be significantly associated with chemo- and radio-resistance and poor prognosis among NSCLC patients [ 25 ]. In contrast, several studies have indicated that MCL1 overexpression was a protective factor against breast cancer and can reduce tumor cell proliferation and arrest cell cycle progression [ 26 ]. Due to the small sample size of patients and insufficient sequencing depth in the present study, we cannot draw a sound conclusion that MCL1 contributes to the different outcomes of the patients with two distinct genotypes.…”