Epigenetic Assymetry in Breast Tumors of different Sides

BRANHAM MARIA T; MATHISON ANGELA; URRUTIA RAÚL; CAMPOY, EMANUEL; URRUTIA GUILLERMO; OROZCO JAVIER; ROQUÉ MARIA; LAURITO SERGIO; GAGO FRANCISCO; MAYORGA LUIS S

HOLDERNESS

Conferencia; GORDON CONFERENCE EPIGENETICS; 2017

GORDON

Breast cancer arises through the accumulation of genetic and epigenetic alterations in different cancer related genes. These alterations confer the tumor oncogenic abilities, which can be resumed as cancer hallmarks (CH). We have established by MS-MLPA the methylation profile of CpG sites located within cancer related genes of breast tumors so as to infer their potential impact on 6 CH: i.e. sustained proliferative signaling, evasion of growth suppressors, resistance to cell death, induction of angiogenesis, genome instability and invasion and metastasis. The distribution of the CH profiles was tested by different statistical methods and correlated with clinical-pathological data. Unsupervised HCA revealed that CH profiles segregate in two main groups, which correlate surprisingly with breast laterality (p = 0.05). These observations were validated by qPCR expression analyses on a different cohort of tumors and by silico analyses on gene expression data from TCGA Breast Dataset from left and right breast tumors. We propose that these differences occur due to the different left-right mammary stroma with which the tumoral epigenome interacts. To test this, primary cultures of human breast carcinoma were performed and treated with left-right extracts from bilateral mammary reductive surgeries. In addition, xenograft tumors were obtained from MDA-MB231 cells inoculated in left-right mammary glands of 3 nude mice. Preliminary results of MS-MLPA analyses on 50 genes reveal a several genes with significant methylation differences in both experimental approaches. We show here for the first time, that breast carcinomas arising on different sides of the body present differential cancer traits inferred from methylation and expression profiles and that these differences can be generated experimentally by modulating the epigenome with left-right mammary components. Embryological studies in vertebrates reveal that paired organs present bilateral asymmetries since the establishment of the left-right axis during development. We therefore propose that the laterality of mammary glands can provoke a differential tumor behavior, through different epigenetic alterations. These findings could contribute to a better personalized treatment and serve as proof of principle for other bilateral cancers like lung, testes or kidney.