Mechanisms of inactivation of E-cadherin in breast carcinoma: modification of the two-hit hypothesis of tumor suppressor gene

Abstract

Loss of heterozygosity (LOH) allows the expression of recessive mutation in tumor suppressor genes (TSG). Therefore, on the basis of Knudson's`two-hit' hypothesis for TSG inactivation, the detection of a high LOH frequency in a chromosomal region is considered critical for TSG localization. One of these LOH regions in breast cancer is 16q22.1, which has been suggested to re¯ect the involvement of E-cadherin (E-cad), a cell ± cell adhesion molecule. To con®rm the tumorigenic role of Ecad, 81 sporadic invasive ductal carcinomas (IDCs) of the breast were tested for the`two hits' required to inactivate this gene. A high frequency (37.3%) of LOH was detected in 67 informative tumors, but no mutation was found. To examine the possibility that transcriptional mechanisms serve as the second hit in tumors with LOH, speci®c pathways, including genetic variant and hypermethylation at the promoter region and abnormal expression of positive (WT1) and negative (Snail) transcription factors, were identi®ed. Of these, promoter hypermethylation and increased expression of Snail were found to be common (435%), and to be strongly associated with reduced/negative E-cad expression (P50.05). However, unexpectedly, a signi®cantly negative association was found between the existence of LOH and promoter hypermethylation (P50.05), which contradicts the`two-hit' model. Instead, since they coexisted in a high frequency of tumors, hypermethylation may work in concert with increased Snail to inactivate E-cad expression. Given that E-cad is involved in diverse mechanisms, loss of which is bene®cial for tumors to invade but may also trigger apoptosis, this study suggests that maintaining a reversible mechanism, either by controlling the gene at the transcriptional level or by retaining an intact allele subsequent to LOH, might be important for E-cad in IDC and may also be common in TSGs possessing diverse functions. These ®ndings provide clues to explain why certain TSGs identi®ed by LOH cannot ful®l the two-hit hypothesis. Oncogene (2001) 20, 3814 ± 3823.

Snail Mediates E-Cadherin Repression by the Recruitment of the Sin3A/Histone Deacetylase 1 (HDAC1)/HDAC2 Complex

“…(8,14,23). A large body of evidence accumulated in recent years suggests that epigenetic mechanisms involving chromatin modification, hypermethylation of CpG islands, and/or transcriptional repression are the main mechanisms responsible for E-cadherin silencing in different types of tumors and cancer cell lines (13,14,42). Several transcriptional repressors of E-cadherin have been identified in the last 3 years.…”

“…Several transcriptional repressors of E-cadherin have been identified in the last 3 years. Among them, the transcription factor Snail has been described as a strong repressor of E-cadherin in different murine and human carcinoma and melanoma cell lines and tumors (5,9,11,13,41,48,55) as well as during Drosophila and mouse embryo development (12,25,37,38). An additional member of the Snail family, Slug, has also been reported to act as an E-cadherin repressor (10,22).…”

“…While genetic alterations of the E-cadherin loci have been found only infrequently in tumors, particularly, in lobular breast carcinomas and diffuse gastric carcinomas (6,7,21,44), the majority of carcinomas with downregulated E-cadherin maintain an intact E-cadherin locus. Epigenetic processes involving hypermethylation of the E-cadherin promoter and/or transcriptional alterations have emerged as the main mechanisms responsible for E-cadherin downregulation in most carcinomas (13,14,23,42). Several transcriptional repressors of E-cadherin have been recently identified, including the zinc finger factors Snail (5,11) and Slug (10,22), the two-handed zinc factors ZEB1(␦EF1) and ZEB2 (SIP-1) (15,20), and the bHLH factor E12/E47 (40).…”

Clinical Outcomes of Downregulation of E-cadherin Gene Expression in Non-small Cell Lung Cancer

“…However, E-cadherin promoter hypermethylation is not always associated with loss of expression , and evidence has been presented that E-cadherin expression could be repressed by mechanisms other than promoter hypermethylation (Cheng et al, 2001).…”

Single‐nucleotide polymorphism in the E‐cadherin gene promoter modifies the risk of prostate cancer

“…8,9 This mechanism, however, remains under debate. 10 Disruption of E-cadherin may also play an initiating role in carcinogenesis through the Wnt signaling pathway. 11 To our knowledge, data on these initiating roles of E-cadherin in PCa carcinogenesis are lacking.…”