Somatic mutation and functional polymorphism of a novel regulatory element in the HGF gene promoter causes its aberrant expression in human breast cancer
Jihong Ma, … , Robert Ferrell, Reza Zarnegar
Jihong Ma, … , Robert Ferrell, Reza Zarnegar
Published February 2, 2009
Citation Information: J Clin Invest. 2009;119(3):478-491. https://doi.org/10.1172/JCI36640.
View: Text | PDF
Research Article Oncology

Somatic mutation and functional polymorphism of a novel regulatory element in the HGF gene promoter causes its aberrant expression in human breast cancer

Abstract

The HGF gene is transcriptionally silenced in normal differentiated breast epithelial cells, but its repression fails to occur in mammary carcinoma tissues and cell lines. The molecular mechanisms underpinning aberrant HGF expression in breast cancer cells are unknown. Here we report the discovery of a DNA element located 750 bp upstream from the transcription start site in the human HGF promoter that acts as a transcriptional repressor and is a target of deletion mutagenesis in human breast cancer cells and tissues. This HGF promoter element consists of a mononucleotide repeat of 30 deoxyadenosines (30As), which we have termed “deoxyadenosine tract element” (DATE). Functional studies revealed that truncation mutations within DATE have profound local and global effects on the HGF promoter region by modulating chromatin structure and DNA-protein interactions, leading to constitutive activation of the HGF promoter in human breast carcinoma cell lines. We found that 51% of African Americans and 15% of individuals of mixed European descent with breast cancer harbor a truncated DATE variant (25As or fewer) in their breast tumors and that the truncated allele is associated with cancer incidence and aberrant HGF expression. Notably, breast cancer patients with the truncated DATE variant are substantially younger than those with a wild-type genotype. We also suggest that DATE may be used as a potential genetic marker to identify individuals with a higher risk of developing breast cancer.

Authors

Jihong Ma, Marie C. DeFrances, Chunbin Zou, Carla Johnson, Robert Ferrell, Reza Zarnegar

×

Figure 8

Truncated DATE is associated with high HGF expression in human breast cancer tissues.

Options: View larger image (or click on image) Download as PowerPoint
Truncated DATE is associated with high HGF expression in human breast ca...
(A and B) Representative immunohistochemistry results depicting HGF protein expression in human breast cancer cases with or without truncated DATE. Significantly higher (+++) HGF protein expression was noted in tumors with truncated DATE compared with those with wild-type DATE, which exhibited mostly moderate (++) to weak (+) expression (P = 8.8 × 10–7 using unpaired 2-tailed t test, n = 42; ***P < 0.001) (see also Supplemental Table 2). (C and D) Adjacent normal breast tissues with truncated DATE also exhibit significantly higher HGF expression as compared with those with wild-type DATE (P = 0.003, unpaired 2-tailed t test; n = 42 (Supplemental Table 2). **P < 0.01. Notably, HGF was localized to epithelium in cases with truncated DATE. Scale bars: 40 μM.