© 2000 by Oxford University Press
Journal of the National Cancer Institute, Vol. 92, No. 6, 437,
March 15, 2000
© 2000 Oxford University Press
IN THIS ISSUE |
Cellular retinol-binding protein (CRBP) binds vitamin A and is believed to regulate its uptake and metabolism into biologically active molecules. Kuppumbatti et al. (p. 475) analyzed the expression of CRBP in normal and malignant breast tissues. They found that CRBP was expressed in all normal breast tissue specimens but was not expressed in 24% of cancerous breast tissue specimens. The lack of CRBP was as frequent in invasive lesions as it was in ductal carcinoma in situ. The authors suggest that the loss of CRBP in 24% of human breast cancers implies a link between cellular vitamin A and breast cancer. They further suggest that the loss of CRBP restricts the effects of endogenous vitamin A on breast epithelial cells.
In an accompanying editorial, Spinella and Dmitrovsky (p. 438) discuss the relationship between aberrant retinoid signaling and breast cancer. They also point out the importance of the analysis of CRBP in normal breast tissue and breast carcinoma that identified an association between repressed expression of CRBP and breast carcinoma. The authors believe that these results will stimulate research to further elucidate this association.
"We hypothesize that compound loss of CRBP and RARß [retinoic acid receptor ß] hinders the bioactivity of endogenous vitamin A more extensively than the single loss of either gene."
—Kuppumbatti et al.
Treating DNA Repair-Deficient Cancer Cells
Cancers exhibiting instability of microsatellite DNA sequences are also characterized by their deficiency of DNA mismatch repair, high rate of spontaneous frameshift mutations, and localization to specific tissues like the proximal colon and stomach. Chen et al. (p. 480) tested whether the acridine mutagen ICR191, an exogenous frameshift-inducing agent, would selectively induce mutations in mismatch repair-deficient cells of these cancers. They found that the mutagen ICR191 is fivefold to 10-fold more mutagenic in the mismatch repair-deficient human colon carcinoma cell line HCT116 compared with repair-proficient cells. The authors suggest vulnerability to chemical mutagens may explain the targeting of these cancers to the colon and stomach. They also found that repair-deficient cells are more likely to die at cytotoxic doses of ICR191 than repair-proficient cells. The authors say that frameshift-inducing agents can preferentially kill mismatch repair-deficient cancer cells and may be of promise as model therapeutic compounds.
In an accompanying editorial, Wei et al. (p. 440) discuss further the evidence for and against various mechanisms of DNA repair. They note that the disparity in the roles of DNA repair in cancer susceptibility and drug resistance poses a challenge to translational research.
Contribution to Melanoma Risk Factors in Twins
The relative contributions of heredity and environment on the expression of nevi and freckles, known risk factors for melanoma, are reported. Bataille et al. (p. 457) studied 450 pairs of twins—127 identical (monozygotic) twin pairs and 323 fraternal (dizygotic) twin pairs—and evaluated the respective contributions of genetic and environmental factors on nevus expression. They found that, for twins under 45 years old, environmental effects account for two thirds of the variance in nevus count, while, for twins 45 years or older, additive genetic effects account for more than four fifths of the variance. Furthermore, body site (sun-exposed or sun-protected) produced statistically significant differences in the heritability estimates. The authors suggest that age and body site need to be taken into account in future studies attempting to identify or map melanoma-associated genes.
"This U.K. twin study confirms that genetic factors are very important in the expression of cutaneous traits associated with an increased melanoma risk."
—Bataille et al.
Angiogenesis in Breast Cancer Metastases
Increased angiogenesis—the growth of new blood vessels—in primary tumors has been linked to poor survival among patients with breast cancer. However, the effect on survival of angiogenesis in breast cancer metastases has not been well studied. Guidi et al. (p. 486) measured microvessel density and assessed the presence or absence of angiogenic "hot spots"—areas of intense vascularization—in primary tumors and axillary lymph node metastases from women with invasive metastatic breast cancer. They found that the presence of hot spots in lymph node metastases, but not in primary tumors, was associated with decreased disease-free survival and overall survival; increased microvessel density in the metastases was similarly associated with decreased overall survival. The authors conclude that assessing angiogenesis in breast cancer metastases may be clinically useful.
Human Papillomavirus Infection in Costa Rica
Human papillomavirus (HPV) is the main cause of cervical neoplasia. Herrero et al. (p. 464) report the results of a population-based study of the prevalence of the various types of HPV in Guanacaste, Costa Rica, a population at high risk for cervical cancer. In healthy women, HPV infection rates peaked in women younger than 25 years and again in women older than 55 years; the HPV types found were predominantly non-cancer associated. In women with cervical abnormalities, there was a strong predominance of HPV16, which is cancer associated. HPV was found in 88% of women with high-grade cervical lesions and in 89% of women with cancer. The authors suggest that these results may help formulate a vaccine against the correct combination of HPV types that may prevent most cases of cervical disease in this region.
"This study provides further evidence for the role of HPV in cervical carcinogenesis, as demonstrated by high ORs [odds ratios] and attributable fractions associated with various pathologic states, particularly the most advanced lesions."
—Herrero et al.
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