HOX gene methylation status analysis in patients with hereditary breast cancer

Abstract

Cancer development is related not only to genetic alterations but also to aberrant epigenetic changes that could lead to heritable gene patterns critical for neoplastic initiation and progression. Knowledge of epigenetic regulation in cancer cells is useful for both the understanding of carcinogenesis and for the possibility of using epigenetic drugs. HOX genes deregulation have a crucial role in oncogenesis process and tumor suppression. In this report, the methylation of HOXA1, HOXA9, HOXA10, HOXB13, HNF1B, OTX1, TLX1 genes have been analyzed in patients with hereditary breast cancer. This is the first study analyzing BRCA mutational status of patients with respect to methylation of HOX genes. HOXA10 has been found to be methylated in all patients analyzed but never in healthy subjects. With respect to clinical pathological information, hypermethylation of all studied genes, with the exception of OTX1, was significantly associated with absence of HER2 neu expression (Po0.05). Moreover, hypermethylation of HOXB13, HOXA10 and HOXA1 was associated with a high proliferation index (Mib1X10%, Po0.05) and hypermethylation of HOXB13 and HOXA10 also with high expression of estrogen and progesterone receptors. These preliminary data suggest a possible involvement of HOX genes in familial breast cancer as marker helpful to identify high-risk patients.HOX genes have a crucial role not only in development, receptor signaling, differentiation, motility and angiogenesis, but also in apoptosis; thus, alterations in their expression could have a role in both oncogenesis and tumor suppression and, consequently, in diagnosis and therapy. In particular, HOX gene methylation is atypical in breast cancer tissue compared with normal epithelia 1 and is linked to malignant transformation and tumor aggressiveness. 2 The aim of this study was to analyze the methylation status of a group of HOX genes in familial breast cancer to understand a possible role of their epigenetic regulation with respect to BRCA1-2 mutational status. In fact, it is already known that HOXA9 overexpression slows breast cancer progression, binding the 5 0 promoter region of BRCA1 then modulating its expression. 2 For this reason, methylation of the regulatory genes HOXA1, HOXA9, HOXA10, HOXB13, HNF1B, OTX1, TLX1 has been investigated in high-risk subjects with a familial history of hereditary breast and/or ovarian cancer, with these genes resulting highly involved in breast cancer. 3,4 This is the first study analyzing BRCA mutational status with respect to methylation of HOX genes in hereditary breast cancer subjects.A total of 24 subjects (19 breast cancer affected and 5 healthy relatives from high-risk familial breast cancer) coming from the genetic counseling program of the National Cancer Research Centre of Bari, and a pool of 9 healthy unrelated controls without breast cancer were enrolled. Among the group of 24, subjects #10, #11, #12, #13 and #20 were healthy, BRCA mutated and with a strong history of breast cancer, whereas patients #3, #8 and #23 also had...

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