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.

Estrogen has been suggested to trigger breast cancer development via an initiating mechanism involving its metabolite, catechol estrogen (CE). To examine this hypothesis, we carried out a multigenic case-control study of 469 incident breast cancer patients and 740 healthy controls to define the role of important genes involved in the different metabolic steps that protect against the potentially harmful effects of CE metabolism. We studied the 3 genes involved in CE detoxification by conjugation reactions involving methylation (catechol-O-methyltransferase, COMT), sulfation (sulfotransferase 1A1, SULT1A1), or glucuronidation (UDP-glucuronosyltransferase 1A1, UGT1A1), one (manganese superoxide dismutase, MnSOD) involved in protection against reactive oxidative species-mediated oxidation during the conversion of CEsemiquinone (CE-SQ) to CE-quinone (CE-Q), and 2 of the glutathione S-transferase superfamily, GSTM1 and GSTT1, involved in CE-Q metabolism. Support for this hypothesis came from the observations that (i) there was a trend toward an increased risk of breast cancer in women harboring a greater number of putative high-risk genotypes of these genes (p < 0.05); (ii) this association was stronger and more significant in those women who were more susceptible to estrogen [no history of pregnancy or older (>26 years) at first full-term pregnancy (FFTP)]; and (iii) the risks associated with having one or more high-risk genotypes were not the same in women having experienced different menarche-to-FFTP intervals, being more significant in women having been exposed to estrogen for a longer period (>12 years) before FFTP. Furthermore, because CE-Q can attack DNA, leading to the formation of double-strand breaks (DSB), we examined whether the relationship between cancer risk and the genotypic polymorphism of CE-metabolizing genes was modified by the genotypes of DSB repair genes, and found that a joint effect of CE-metabolizing genes and one of the two DSB repair pathways, the homologous recombination pathway, was significantly associated with breast cancer development. Based on comprehensive CE metabolizing gene profiles, our study provides support to the hypotheses that breast cancer can be initiated by estrogen exposure and that increased estrogen exposure confers a higher risk of breast cancer by causing DSB to DNA.Key words: breast cancer; estrogen; catechol estrogen; polymorphism; molecular epidemiology An increased risk of breast cancer due to prolonged exposure to estrogen has been well documented by epidemiological observations showing that estrogen-related risk factors, including age at menarche, age at menopause, parity and age at first full-term pregnancy (FFTP), are significantly associated with breast cancer risk. 1,2 Why estrogen exposure should increase breast cancer risk is an intriguing question that has not been conclusively answered. One simple explanation is that the proliferative effect of estrogen on breast epithelium promotes the growth of tumor cells, leading to progression of breast cancer. [3...

Severe head injury, a skull fracture contralateral to the original hematoma, intraoperative brain protrusion, and a poor outcome are typical clinical findings in this disorder. In patients with acute SDH and a contralateral skull fracture, immediate postoperative CT scan is indicated to evaluate this rare but potentially lethal complication. According to the findings of the postoperative CT scan, the neurosurgeon can make an appropriate strategy of treatment promptly. Early detection and prompt treatment may improve the poor outcome in this group of patients.