Expression of the hypermethylated in cancer gene (HIC-1) is associated with good outcome in human breast cancer

Abstract

Summary A new cancer gene, HIC-1 (Hypermethylated in Cancer) telomeric to p53 on chromosome 17p may be of clinical importance in sporadic breast cancer. Regional DNA hypermethylation of 17p13.3 resulting in suppression of gene expression has been shown to precede 17p structural changes in human carcinogenesis. In addition, loss of heterozygosity studies have suggested clinically significant involvement of a gene on 17p13.3 associated with poor prognosis in breast cancer. Using RT-PCR analysis, we demonstrate that the MCF7 (wild type p53) cell line expressed HIC-1 transcripts but the MDAMB231 (mutant p53) cell line did not, suggesting loss of HIC-1 expression and p53 malfunction may be synergistic events in sporadic breast cancer. HIC-1 expression was examined using RT-PCR on RNA extracted from 50 primary untreated, human breast cancers and was detected in only 7/50 (14%) cancers. All seven patients with HIC-1 expression were alive without disease recurrence after 8 years follow-up and 5/7 had detectable p53 wild type mRNA expression. This suggests that retained HIC-1 expression may offer a survival advantage. However the seven cancers had 17p13.3 loss of heterozygosity (LOH; four patients), a feature previously associated with poor prognosis, or were homozygous (three patients) suggesting there may be two genes at 17p13.3 involved in breast carcinogenesis. Using a demethylating drug 5-aza-2′-deoxycytidine (DeoxyC), HIC-1 expression was restored in the MDAMB231 cells, also suggesting restoration of HIC-1 function by reversing HIC-1 hypermethylation may offer a therapeutic avenue in breast cancer.

Prognostic and diagnostic relevance of hypermethylated in cancer 1 (HIC1) CpG island methylation in renal cell carcinoma

“…Fleuriel et al proposing an association of HIC1 hypermethylation with aggressive tumor behavior. However our finding that quantitatively measured HIC1 CGI methylation is an independent predictor of recurrence-free survival agrees well with the results of Fleuriel et al describing a relationship with poor prognosis of patients (17,18,23,29,(36)(37)(38).…”

Identification of the p53 family-responsive element in the promoter region of the tumor suppressor gene hypermethylated in cancer 1

“…In addition, a survey of sporadic breast cancer revealed a similar synergistic effect combining loss of HIC1 expression and p53 malfunction (Nicoll et al, 2001). Moreover, it has been recently reported that sirtuin-1 (SIRT1), the human homolog of the yeast silent information regulator 2a, is negatively regulated by HIC1 at the transcriptional level (Chen et al, 2005).…”

Loss of Hypermethylated in Cancer 1 (HIC1) in Breast Cancer Cells Contributes to Stress-induced Migration and Invasion through β-2 Adrenergic Receptor (ADRB2) Misregulation

“…In these tissues, HIC1 is already hemi-methylated in normal conditions and its extinction is correlated with the aggressiveness of tumors (2,4). The identification of HIC1 target genes is thus a crucial step in understanding how its inactivation could contribute to tumorigenesis.…”

“…HIC1 is hemi-methylated in normal breast tissue and is found to be epigenetically or deletionally (loss of heterozygosity) inactivated in many cases of breast carcinomas (2,3). Expression of HIC1 is associated with an improved prognosis in human breast cancer (4).…”