Breast cancer risk associated with genotypic polymorphism of the genes involved in the estrogen-receptor-signaling pathway: A multigenic study on cancer susceptibility
Journal
Journal of Biomedical Science
Journal Volume
13
Journal Issue
3
Pages
419-432
Date Issued
2006
Author(s)
Yu J.-C.
Hsu H.-M.
Chen S.-T.
Hsu G.-C.
Hou M.-F.
Fu Y.-P.
Cheng T.-C.
Wu P.-E.
Shen C.-Y.
Abstract
The reproductive hormone, estrogen, contributes to the development of breast cancer by binding to the estrogen receptor (ER) in the nucleus, triggering cell growth and tumor promotion. In addition to its role in regulating target genes and signaling pathways involved in cell cycle progression, the ER-signaling pathway may regulate the expression of chromatin-remodeling gene, Metastasis-associated 3 (MTA3), or interact with chromatin-remodeling protein, Metastasis-associated 1 (MTA1). The invasion-suppressor gene, E-Cadherin (E-Cad), has recently been identified as a downstream target gene regulated by the ER-MTA3 pathway via the transcriptional repressor, Snail, and the ER-MTA3-Snail-E-Cad pathway has therefore been evoked to explain the clinical observation that ER expression in breast cancer is generally associated with a better clinical outcome. Since E-Cad may play an initiating role during breast tumorigenesis, we hypothesized that this ER-signaling pathway may also determine susceptibility to breast cancer, and examined this in a multigenic case-control study of 468 incident breast cancer patients and 470 healthy controls by genotyping the single nucleotide polymorphisms (SNPs) in five genes (ER, MTA3, Snail, E-Cad, and MTA1) in the ER-signaling pathways. Support for this hypothesis came from the observations that (a) with the exception of Snail, which interacted differently with reproductive risk factors in relation to breast cancer risk, there was a joint effect of the SNPs of these genes and estrogen-related risk factors (age at first full-term pregnancy and obesity, measured by the body mass index) on breast cancer risk (p < 0.05); (b) a trend toward increased risk of developing breast cancer was seen in women harboring a greater number of putative high-risk genotypes of these genes in ER-signaling pathways; (c) this association between risk and the number of putative high-risk genotypes was stronger and more significant in women thought to have experienced higher estrogen level, i.e., obese women; and (d) the risk effect conferred by obesity was only significant in women with a higher number of putative high-risk genotypes of the ER-signaling genes. These epidemiological findings highlight the role of newly identified novel ER-related pathways in breast cancer development and provide a more comprehensive picture of the tumorigenic effect of estrogen in breast cancer development. ? 2006 National Science Council.
SDGs
Other Subjects
estrogen; estrogen receptor; gene product; metastasis associated 1 protein; oncoprotein; transcription factor Snail; unclassified drug; uvomorulin; adult; article; body mass; breast cancer; breast carcinogenesis; cancer risk; cancer susceptibility; case control study; cell growth; cell nucleus; chromatin assembly and disassembly; controlled study; DNA polymorphism; epidemiological data; estrogen activity; female; gene expression; gene targeting; genotype; high risk patient; human; human tissue; hypothesis; major clinical study; metastasis associated 3 gene; obesity; oncogene; pregnancy; priority journal; risk factor; signal transduction; single nucleotide polymorphism; statistical significance; tumor promotion; Breast Neoplasms; Cadherins; Case-Control Studies; Female; Genetic Predisposition to Disease; Genotype; Histone Deacetylases; Humans; Neoplasm Metastasis; Neoplasm Proteins; Neoplasms; Polymorphism, Genetic; Receptors, Estrogen; Repressor Proteins; Signal Transduction; Gastropoda
Type
journal article