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© Oxford University Press 2007.
IN THIS ISSUE
Indentification of New Tumor Suppressor Gene for Lung CancerMany genetic and epigenetic changes are usually necessary for lung cancers to develop, including the inactivation of tumor suppressor genes. The human G protein-coupled receptor C type 5A (GPRC5A) gene is expressed at higher levels in normal lung cells than in lung tumor cells. To find out whether it is a tumor suppressor, Tao et al. (p. 1668) developed a knockout mouse model and compared GPRC5A expression in normal human lung tissues and lung cancers. The Gprc5A knockout mice developed more lung tumors (76% developed adenomas and 17% adenocarcinomas) than the wild-type mice (10% developed adenomas) during the 2-year study period. In human tissues, GPRC5A expression was lower in most of the lung cancers examined than in normal lung tissue. The authors conclude that Gprc5A acts as a lung cancer tumor suppressor in the mouse and that the human homolog may have a similar function in human lung cancer.
In an editorial, Sporn (p. 1654) highlights the contributions of this study and writes that the Gprc5A knockout mouse model will be useful in elucidating the multistep process of lung carcinogenesis.
Molecular Basis for ER
Deficiency in BRCA1-Linked Breast Cancer
Most BRCA1 mutant breast tumors do not express estrogen receptor alpha (ER), whereas most sporadic tumors express both ER and wild-type BRCA1. Hosey et al. (p. 1683) performed in vitro studies of human breast cancer cells to determine the mechanism for this disparity in ER gene expression. They found that the BRCA1 protein mediates activation of the gene encoding ER and that expression of exogenous ER in BRCA1-depleted breast cancer cells increased their sensitivity to the antiestrogen drug fulvestrant. The authors conclude that the BRCA1 protein alters the response of breast cancer cells to antiestrogen therapy by directly modulating ER expression.
In an editorial, Jordan (p. 1655) discusses the prominence of the estrogen receptor as a target in breast cancer and the central questions about its origins and efficacy as a therapeutic target. He points out how seemingly disparate discoveries can converge to shed light on complex mechanisms in biology.
Ultrasound versus CA-125 for the Diagnosis of Adnexal Masses
Both gray-scale and Doppler ultrasound findings evaluated by an experienced examiner and pre-operative serum CA-125 levels can discriminate between benign and malignant adnexal masses (ovarian, paraovarian, or tubal masses). In a large multicenter study, Van Calster et al. (p. 1706) compared these methods with post-operative histologic findings for adnexal masses. Ultrasound examination by an experienced examiner correctly classified more masses as benign or malignant than serum CA-125, and it also often correctly identified the histologic type of the mass. The accuracy of an ultrasound scan depends on the experience of the examiner, so physicians still lack confidence in ultrasound reports. The authors conclude that more effort and resources are needed to improve training in gynecological ultrasound to increase confidence in the technique.
Predicting Breast Cancer Risk by Hormone Receptor Status
Methods are needed to rapidly identify postmenopausal women who would benefit from risk reduction interventions. Chlebowski et al. (p. 1695) developed a prediction model for breast cancer using data from the observational study and three clinical trial cohorts in the Women’s Health Initiative. Their model uses only three factors—age, breast cancer in first-degree relatives, and previous breast biopsy—and performed nearly as well as the Gail model for predicting the risk of estrogen receptor (ER)–positive breast cancer in postmenopausal women. The authors conclude that their new model with fewer variables may be as effective at identifying postmenopausal women at high risk of ER-positive breast cancer as the Gail model. They also suggest that it may provide a simpler approach for identifying women who would benefit from risk reduction interventions.
In an editorial, Gail (p. 1657) notes that the results illustrate the promise and difficulty of estimating absolute risk in breast cancer subtypes. He calls for more studies of this type in women 50 years or older and in women younger than 50 years.
Challenges in Assigning Patients to Previously Identified Subtypes
The expression levels of multiple genes in a tumor sample—as determined using microarray technology—have been used to identify subtypes of breast and other cancers. An analytical procedure called the method of centroids has been used by many investigators to assign new tumor samples to previously identified cancer subtypes. Lusa et al. (p. 1715) used this method to classify breast cancer samples with known characteristics. They then explored the effects of data normalization methods, subtype prevalence, and systematic differences between datasets on the accuracy of the subtype assignments. The authors suggest that their results underscore the need for careful attention to the comparability of patient populations and data in attempts to assign new patients to cancer subtypes previously identified in an independent dataset.
Amelioration of ZD6126-Induced Cardiac Toxicity in Rats
The antivascular agent ZD6126 selectively destroys the tumor vasculature, but it is also associated with adverse cardiovascular effects. Gould et al. (p. 1724) investigated the mechanisms underlying these adverse effects in rats by continuously monitoring their heart rate and blood pressure and assessing their heart histopathology and plasma levels of the cardiac biomarker troponin T. ZD6126 induced a transient increase in blood pressure and tachycardia that was associated with increases in circulating troponin T levels and myocardial fiber necrosis. Pretreatment of rats with atenolol and nifedipine lessened the acute hemodynamic changes and prevented ZD6126-induced increases in both troponin T and myocardial necrosis, but it did not prevent ZD6126-induced tumor necrosis in an Hras5 tumor xenograft model in nude rats. The authors conclude that ZD6126-induced changes are a prerequisite for cardiac damage in rats.
Possible Association Between Smoking and Rectal Cancer
Evidence linking cigarette smoking to colorectal cancer risk is inconsistent. Paskett et al. (p. 1729) investigated this relationship among the 1,242 women in the Women's Health Initiative who were diagnosed with colorectal cancer after an average follow-up of 7.8 years. Statistically significant associations were observed between most measures of cigarette smoking and increased risk of invasive colorectal cancer. Current smoking was associated with a statistically significantly increased risk of rectal cancer but not of colon cancer. The authors conclude that active cigarette smoking may be a risk factor for rectal cancer.
Related Articles in JNCI
CiteULike 
Connotea 
Del.icio.us What's this?
J Natl Cancer Inst 2007 99: 1729-1735.
J Natl Cancer Inst 2007 99: 1706-1714.
J Natl Cancer Inst 2007 99: 1724-1728.
Deficiency in BRCA1-Linked Breast Cancer
J Natl Cancer Inst 2007 99: 1683-1694.
J Natl Cancer Inst 2007 99: 1668-1682.
J Natl Cancer Inst 2007 99: 1715-1723.
J Natl Cancer Inst 2007 99: 1695-1705.
J Natl Cancer Inst 2007 99: 1654-1655.
J Natl Cancer Inst 2007 99: 1657-1659.
J Natl Cancer Inst 2007 99: 1655-1657.
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