A healthy diet and lifestyle protect against a wide range of diseases, and new research presented at the American Association for Cancer Research 2008 Annual Meeting, April 12-16, shows that cancer is no exception. Researchers demonstrate how excessive alcohol drinking could lead to an increased risk of breast cancer, how consuming too many calories may increase one’s risk for melanoma, and why with folic acid, timing is everything for colon cancer prevention.

Alcohol consumption and risk of breast cancer in postmenopausal women: the NIH-AARP Diet and Health Study: Abstract 4168

One of the largest studies of its kind has found that alcohol is a substantial risk factor for development of the most common type of breast cancer – the 70 percent of tumors that are classified as positive for both the estrogen and progesterone receptors (ER+/PR+).

Researchers report that even moderate alcohol consumption, defined as one or two drinks per day, increased risk of developing this kind of cancer, and the more a woman drank, the higher her risk. Compared to women who did not drink at all, women who had three or more glasses of alcohol daily had as much as a 51 percent increased risk of ER+/PR+ breast cancer.

“This suggests that a woman should evaluate consumption of alcohol along with other known breast cancer risk factors, such as use of hormone replacement therapy,” said the study’s first author, Jasmine Q. Lew, a fourth-year medical student at the University of Chicago who is conducting this research as a recipient of the Howard Hughes Medical Institute-National Institutes of Health Research Scholarship at the National Cancer Institute’s (NCI) Division of Cancer Epidemiology and Genetics.

Lew and her research colleagues from NCI say their analysis could not support a definitive conclusion as to whether alcohol influences development of other breast cancer tumor types. “But we have enough numbers to study alcohol’s influence on ER+/PR+ breast cancer,” she said.

Epidemiologic studies have long suggested that use of alcohol may increase a woman’s risk for developing breast cancer, and laboratory studies have shown that alcohol increases the amount of estrogen metabolites available in a woman’s body, which can then act as a fuel for hormone-sensitive breast cancer. But few studies have looked at alcohol’s effect on tumor type.

In this study, the researchers reviewed data from the NIH-AARP Diet and Health Study, which began in 1995. Lew and her colleagues analyzed 184,418 postmenopausal women who enrolled in this cohort study, and who answered questions about their daily alcohol consumption. During an average of seven years of follow-up, they found that 70 percent of women in the study drank alcohol; the average amount was a little less than a drink a day. Overall, the authors found that moderate drinking in women increased risk of developing breast cancer.

They then identified 5,461 cases of invasive breast cancer, for which they had tumor type information on 2,391 cases. In all, they analyzed data on 1,641 ER+/PR+, 366 ER-/PR-, 336 ER+/PR-, and 48 ER-/PR+ cases of invasive breast cancer.

The researchers found that ER+/PR+ cancers showed a stronger association with alcohol than that seen in the overall group. Compared to non-drinkers, women who consumed less than one drink daily, one to two drinks, and three or more daily drinks, the increase in relative risk for developing ER+/PR+ breast cancer was 7 percent, 32 percent, and 51 percent, respectively. Although the data suggested increased risks among the women with ER+/PR- breast cancer, the number of cases was relatively small, and this finding was not statistically significant.

The increased risk of invasive breast cancer was observed across different types of alcohol consumed.

“Our study at this point provides evidence for the notion that alcohol affects estrogen metabolism, which increases risk of hormone sensitive breast cancer,” Lew said. “Still, more study is needed to clarify the effect of alcohol on other tumor types.”

Association Between ADH1B and ADH1C Haplotype Tag SNPs and Breast Cancer Risk, and the Interaction with Alcohol Drinking: Abstract 5814

Specific variations within two genes involved with alcohol metabolism are associated with an increased risk for breast cancer in postmenopausal women, according to a new study.

The work, conducted by research groups led by Peter Shields, M.D., professor of medicine and oncology at Georgetown University’s Lombardi Comprehensive Cancer Center and Jo Freudenheim, Ph.D., chair of social and preventive medicine at the State University of New York at Buffalo, indicates that sequence variations within the genes

ADH1B and ADH1C may as much as double a postmenopausal woman drinker’s risk for breast cancer.

“We found that variations in two genes coding for the alcohol dehydrogenase enzyme increase the risk of breast cancer among women who drink,” said lead author Catalin Marian, M.D., Ph.D., a research instructor of cancer genetics and epidemiology at Georgetown. “The higher their alcohol consumption, the higher their risk.”

Marian and colleagues evaluated data from participants in the Western New York Exposure and Breast Cancer (WEB) Study, a population-based case-control study of breast cancer conducted by Freudenheim in women ages 35 to 79 from two western New York counties between 1996 and 2001. Women with primary, histologically confirmed breast cancer served as cases. Healthy control participants were randomly selected and matched to cases by age, race and county of residence.

The research team analyzed DNA samples taken from 991 women with breast cancer and 1,698 controls. They found that variations within the DNA sequences rs1042026 in the gene ADH1B and rs1614972 in the gene ADH1C were associated with an increased breast cancer risk for postmenopausal women. Within the rs1042026 sequence, the risk of breast cancer for women who had a variant form of the gene and who drank alcohol was nearly twice that of women who abstained. The risk of breast cancer increased with the level of alcohol consumption.

Within the rs1614972 sequence, the variant form of the gene offered a protective effect against breast cancer that varied inversely proportional with the drinking level. The more alcohol women drank, the less protective the effect and the higher their risk of developing breast cancer.

Marian cautions that the work needs to be explored further and replicated by other studies, as the research showed these sequence variations were associated with increased risk of breast cancer but were not necessarily biologically responsible for this effect.

“These two genes encode for enzymes involved in the metabolization of alcohol, so variations in these genes can increase or decrease the rate of alcohol metabolism,” Marian said. “We have to keep in mind that the gene sequence variations we observed are not located directly in coding regions, but they may be associated and inherited together with other variations that have this effect on the enzyme function.”

Dietary energy balance modulates multistage epithelial carcinogenesis in mouse skin: Abstract 1604

New data suggest that dietary energy balance may affect the risk for skin tumor development. Researchers believe that these effects of dietary energy balance are mediated by changes in signaling through the epidermal growth factor receptor (EGFR) and the insulin-like growth factor 1 receptor (IGF-1R).

“We have demonstrated that dietary energy balance directly modulates activation of cell surface receptors, specifically the EGFR and the IGF-1R, which subsequently affects signaling through downstream pathways, such as Akt and mTOR. Negative energy balance inhibits, while positive energy balance enhances, signaling through these pathways, thereby modulating cellular growth, proliferation, and survival,” said Tricia Moore, lead author of the study.

Dietary energy balance refers to the balance between caloric intake and energy expenditure, according to the report. Previous findings from both epidemiological and experimental studies suggest chronic positive energy balance, which can lead to obesity, increases the risk of developing multiple cancers. However, a negative energy balance state, as induced by calorie restriction, decreases these risks in most instances, the researchers said.

In the present study, the researchers used a two-stage skin carcinogenesis model to examine the effects of both positive and negative dietary energy balance on skin tumor promotion and progression. Groups of female mice received 25 nmol of 7,12-dimethylbenz(a)anthracene (DMBA), a cancer inducing chemical, and were then placed on one of four dietary treatment regimens to generate either a positive or negative energy balance state. After four weeks on their respective diets, the mice received two other cancer inducing chemicals (acetone, 3.4 nmol or 6.8 nmol 12-O-tetradecanoylphorbol-13-acetate (TPA)) twice weekly for the duration of the study.

Negative energy balance, as induced by both 15 percent and 30 percent calorie restriction, led to inhibition of papilloma (benign skin tumors that can potentially lead to skin cancer) formation, depending on TPA dose, when compared to either positive energy balance inducing diet. Although tumor multiplicity, as measured by papillomas per mouse, was slightly higher among those receiving the more calorie dense fat diet, this was not different from the less calorie dense fat diet with either dose of TPA, the researchers noted. The impact of dietary energy balance manipulation on the conversion of papillomas to squamous cell carcinomas in this model of multistage skin carcinogenesis is also being assessed.

These researchers have also shown that dietary energy balance alters signaling through the Akt and mTOR pathways, both of which are related to TPA-mediated skin tumor development. They propose that the mechanism for the effect of dietary energy balance on Akt and mTOR signaling may be mediated, in part, by changes in serum IGF-1 levels, which then alters signaling through the IGF-1R and EGFR.

"These findings will provide the basis for future translational studies targeting the Akt/mTOR pathway via combinations of lifestyle (e.g., moderate calorie restriction regimens) and pharmacologic approaches for the prevention and control of obesity-related epithelial cancers in humans," said John DiGiovanni, Ph.D., director of M. D. Anderson Cancer Center – Science Park Research Division, in whose lab this work is being conducted.