Environmental Factor, September 2006, National Institute of Environmental Health Sciences
DERT Papers of the Month
By Jerry Phelps
Polymorphisms in Nucleotide Excision Repair Genes Modify Breast Cancer Risk in Smokers
Breast cancer occurs at different rates in different racial groups. NIEHS-supported researchers at the University of North Carolina determined that African-American women smokers with specific combinations of polymorphisms in nucleotide excision repair genes are more susceptible to breast cancer than white women who smoke.
Nucleotide excision repair is the primary means by which smoking-induced DNA damage is repaired. Smoking is a recognized risk factor for lung, head and neck and other cancers, but the relationship between smoking and breast cancer is unclear. There are several known polymorphisms in genes involved in nucleotide excision repair. These investigators conducted a genetic epidemiologic study aimed at determining whether genetic polymorphisms alter the association between smoking and breast cancer.
They found that, in general, smoking was a stronger risk factor for breast cancer in African-American women than white women. The risks increased even more for African-American women with particular patterns of polymorphisms when combined with different smoking characteristics such as amount of smoking, duration, and age at smoking initiation.
The investigators claim that this is the first study to examine nucleotide excision repair polymorphisms as susceptibility factors for breast cancer in combination with smoking. Further studies with larger numbers of participants are needed to confirm these results.
Citation: Mechanic LE, Millikan RC, Player J, de Cotret AR, Winkel S, Worley K, Heard K, Heard K, Tse CK, Keku T. 2006. Polymorphisms in nucleotide excision repair genes, smoking and breast cancer in African Americans and whites: a population-based case-control study. Carcinogenesis 27(7):1377-1385.
Identification of Lung Tumor Susceptibility Genes
Ming You of the Washington University School of Medicine reports in the August edition of Nature Genetics the discovery of new lung cancer susceptibility genes along with advances in the technique of whole-genome association analyses to identify candidate genes. Whole-genome association studies are a comprehensive approach to testing the hypothesis that common alleles contribute to genetically inherited diseases.
Using inbred mice, You and his research team reproduced the pulmonary adenoma susceptibility 1 (Pas1) locus previously identified in other studies. Their efforts narrowed this locus to a region of DNA of less than 500,000 bases, which contains at least two genes that are strong lung-cancer susceptibility gene candidates. Then using knock-out mice, transgenic mice missing these genes, the team found that cancer susceptibility candidate 1 (Casc1) knock-out mice are susceptible to chemical induction of lung-tumors. They also identified three other locations for possible lung cancer genes. One of these genes, named lung adenoma susceptibility candidate 1 (Lasc1), was previously unknown. They also determined that a specific allele of this gene "preferentially promotes lung tumor cell growth."
These findings are significant because they represent progress in identifying genes whose human forms may predispose some individuals to lung cancer. They also demonstrate that as new resources and denser single nucleotide polymorphism maps become available, mouse models of human diseases will be central to disease susceptibility gene discovery in whole-genome association analyses.
Citation: Liu P, Wang Y, Vikis H, Maciag A, Wang D, Lu Y, Liu Y, You M. 2006. Candidate lung tumor susceptibility genes identified through whole-genome association analyses in inbred mice. Nat Genet 38(8):888-895.
Protecting Human Melanocytes from UV-Induced DNA Damage
Researchers at the University of Cincinnati developed three peptides that mimic a naturally occurring hormone that results in tanning and enhances the DNA repair capacity in pigment producing cells known as melanocytes.
The natural hormone is alpha melanocyte stimulating hormone (a-MSH), which is a peptide hormone made up of 13 amino acids. It is released from the pituitary gland and stimulates melanocytes to produce the pigment melanin which causes tanning after exposure to the sun. The synthetic peptides, or analogs, are each four amino acids in length and share a common sequence with the natural hormone. Two of the analogs were found to be more potent than a-MSH in stimulating production of melanin, reducing apoptosis and release of hydrogen peroxide, and repairing UV-induced DNA damage in cultured human melanocytes.
The authors believe that these analogs could be developed into topically applied creams that would protect the skin from UV-induced cancers. This could be especially important for individuals at high risk of melanoma such as those with a family history of the disease or life-styles or occupations that cause extended sun exposure.
Melanoma results when melanocytes in the skin develop DNA damage that overwhelms their inherent DNA repair capacity. Melanoma is the deadliest form of skin cancer. Since there is no known cure, limiting sun exposure and the use of sunscreens, has become the primary focus of preventing the disease. Melanoma incidence is increasing, especially in parts of the world where sun exposure is high. For instance in Australia, 1 in 35 women and 1 in 25 men will have at least one melanoma during their lifetime.
Citation: Abdel-Malek ZA, Kadekaro AL, Kavanagh RJ, Todorovic A, Koikov LN, McNulty JC, Jackson PJ, Millhauser GL, Schwemberger S, Babcock G, Haskell-Luevano C, Knittel JJ. 2006. Melanoma prevention strategy based on using tetrapeptide alpha-MSH analogs that protect human melanocytes from UV-induced DNA damage and cytotoxicity. FASEB J 20(9):1561-1563.
Loss of Liver NF-kappaB Activity Boosts Chemical Carcinogenesis
New research findings from the University of California at San Diego shed light on the link between chronic inflammation and development of liver cancer. Michael Karin and colleagues have been studying a transcription factor known as NF-kappaB; previous research has identified it as an important component in the inflammation/cancer connection. Using a transgenic mouse strain lacking an enzyme that activates NF-kappaB, they have determined that chemically-induced liver cancer occurs through prolonged activation of another enzyme known as c-Jun N-terminal kinase 1 (JNK1).
The most common form of liver cancer is hepatocellular carcinoma (HCC), which is the third leading cause of cancer deaths worldwide. HCC has been linked to chronic infections of hepatitis B and C virus. Although HCC is relatively rare in the U.S., its incidence is growing rapidly due to the increase in cases of hepatitis C. HCC has also been linked to exposure to genotoxic and cytotoxic factors such as high alcohol consumption and aflatoxin, which cause chronic inflammation and liver injury.
Karin and colleagues point out that "the exact cellular and molecular mechanism through which JNK1 promotes tumor growth, progression, and angiogenesis requires further investigation." However they conclude that despite the uncertainties in the mechanism, these results "strongly suggest that JNK1 is an important target for the development of chemopreventive and therapeutic measures for reducing the emergence of HCC in the context of chronic liver injury and slowing the progression of preexisting tumors."
Citation: Sakurai T, Maeda S, Chang L, Karin M. 2006. Loss of hepatic NF-kappaB activity enhances chemical hepatocarcinogenesis through sustained c-Jun N-terminal kinase 1 activation. Proc Natl Acad Sci U S A 103(28):10544-10551.