The q24 band of chromosome 8(8q24)is frequently amplified in human cancers including breast cancer,and several SNPs(single nucleotide polymorphisms)at 8q24,including rs13281615,have been identified for their association with cancer risks.These SNPs are in a"gene desert"region,and their functions in cancer development remain to be illustrated,although several of the SNPs appear to influence the genes in the"desert"in a long-range manner,including the v-myc avian myelocytomatosis viral oncogene homolog(MYC)and the nonprotein coding plasmacytoma variant translocation 1(PVT1),both of which have been implicated in human cancers.In the current study,we examined rs13281615 for its potential role in breast cancer using normal and cancer tissues from 121 Chinese women with breast cancer.In addition to confirming the association of the GG genotype of rs13281615 with breast cancer risk,we found that germline GG genotype was significantly associated with estrogen receptor(ER)positivity,higher tumor grade and higher proliferation index.We also found frequent somatic mutations(22/121 or 18.2%)of this SNP in breast cancer.Interestingly,the majority of the mutations(17/22 or 77%)involved a G/A change,resulting in a decrease in the number of cancers with the GG risk genotype and subsequent loss of GG association with higher tumor grade and proliferation index in cancers.Furthermore,PVT1 expression was increased in cancers,and the increase was associated with the GG genotype of rs13281615.These results suggest that the GG genotype of SNP rs13281615 plays a role in breast cancer likely by influencing PVT1 expression,and that during oncogenesis,"protective"mutations could occur.
Angiogenesis,a process by which the preexisting blood vasculature gives rise to new capillary vessels,is associated with a variety of physiologic and pathologic conditions.However,the molecular mechanism underlying this important process remains poorly understood.Here we show that histone deacetylase 6(HDAC6),a microtubule-associated enzyme critical for cell motility,contributes to angiogenesis by regulating the polarization and migration of vascular endothelial cells.Inhibition of HDAC6 activity impairs the formation of new blood vessels in chick embryos and in angioreactors implanted in mice.The requirement for HDAC6 in angiogenesis is corroborated in vitro by analysis of endothelial tube formation and capillary sprouting.Our data further show that HDAC6 stimulates membrane ruffling at the leading edge to promote cell polarization.In addition,microtubule end binding protein 1(EB1)is important for HDAC6 to exert its activity towards the migration of endothelial cells and generation of capillary-like structures.These results thus identify HDAC6 as a novel player in the angiogenic process and offer novel insights into the molecular mechanism governing endothelial cell migration and angiogenesis.
