| Breast cancer is currently the most common malignant tumor among women aroundthe world, accounting for23%of the new cancer cases and14%of the cancer deaths.Although the breast cancer incidence was low in China, it had been increasing20~30%in China’s urban registries in the past decade. The etiology of breast cancer iscomplex and multifactorial, possibly being a result of environmental and geneticfactors.Over the pastfew years, genome-wide association studies (GWAS), a powerfulapproach inexploring the genetic determinants of complex diseases, have identifiedapproximately70susceptibility loci of breast cancer, implying an important role ofgenetic factors in the development of breast cancer.However, these loci can interpretless than30%familial risk of breast cancer. Additional efforts on candidate genes thatare crucial in the breast carcinogenesis may be useful to uncover missingheritabilityof breast cancer.Autophagy is a cellular process directed at recycling of cellular proteins andremoval of intracellular microorganisms, which is important for balancing sources ofenergy at critical times in development and in response to nutrient stress.Autophagy-related (ATG) genes were identified in yeast genetics at first, andmorethan two dozen homologs of the yeast ATG genes have been identified in mammals todate.The Beclin1–interacting complex, a regulatory platform, consists of Beclin1,the class III phosphatidylinositol3-kinase (Vps34), and p150.Stimulation of this complex generates phosphatidylinositol-3-phosphate,which promotes autophagos-omal membrane nucleation. It has been proved that many important genes involvingin the regulation process as positive regulators, such as ultraviolet irradiationresistant-associated gene(UVRAG), SH3-domain GRB2-like endophilin B1(SH3GLB1), activating molecule in beclin1-regulated autophagy(AMBRA1),VacuoleMembrane Protein1(VMP1)and tumor protein p53inducible nuclear protein2(TP53INP2).Some of them indicated the activity of tumor suppressing.During the formation of mammalian autophagosomes, two Ubiquitin-like proteinconjugation systems including Atg12-conjugation and LC3-modification are required,and six core genes (ATG3, ATG5, ATG7, ATG10, ATG12and LC3) have been proveninvolving in this process. And several studies were performed to explore themechanisms of them on tumorigenesis.Autophagy indicate an obvioustumor-suppressing role during the early stages oftumorigenesis. For example, loss of Beclin1and Bif-1(Bax interacting factor1) couldenhance the development of breast cancer. Similar important roles of ATG have alsobeen shown in the development of other cancers. These evidences together reveal theimportance of autophagy in carcinogenesis, including breast. However, most ofstudies focused on the associations of polymorphisms in ATG genes and risk oftuberculosis and Crohn’s disease.The role of genetic variants of ATG genes in breastcancer risk is largely unknown.Thus, we have systematically screened23potentially functional polymorphismsin12core autophagy related genes (BECN1, SH3GLB1, UVRAG, AMBRA1,TP53INP2, VMP1, ATG3, ATG5, ATG7, ATG10, ATG12andLC3), and conducted acase-control study including1064breast cancer cases and1073cancer-free controlsfrom Jiangsu province of eastern China to evaluate the associations of these variantswith breast cancer risk.We found that rs7216727in UVRAG and rs1864182andrs10514231in ATG10were significantly associated with risk of breast cancer withper-allele odds ratios (ORs) of0.84(95%confidence interval (CI):0.71-0.99; P=0.040),0.77(95%confidence interval (CI):0.61-0.96; P=0.023) and0.75(95%CI:0.59-0.93; P=0.010), respectively. Similar protective effects for all the three loci were observed between subgroupsstratified by ages at diagnosis/recruitment,menarche and first live birth, and status of menopause, estrogen receptor (ER) andprogesterone receptor (PR). In conclusion, we find three genetic variants rs7126727in UVRAG, rs1864182and rs10514231in ATG10may play an important role in thesusceptibility of breast cancer in Chinese women. |
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