Hypermethylation is a process that causes genes that promote normal cell growth to produce proteins that cause malignant behavior, or unregulated cell growth. Until now, data has been very limited regarding the mechanism and causes of hypermethylation, especially for hypermethylation in breast cancer. The purpose of the current study was to determine how DNA hypermethylation relates to other characteristics of breast tumors.

"It is well known that mutation in genes -- alterations in their sequence -- is one of the characteristics of tumors responsible for some of their disease properties," said Menghua Tao, Ph.D., research assistant professor of social and preventive medicine in the UB School of Public Health and Health Professions and first author on the study.

"In addition, it is now becoming clear that other changes in the DNA may also contribute to the development of cancer."

The researchers analyzed methylation status in three genes, known as E-cadherin, p16 and retinoic acid B2 receptor (RAR-B2), using tissue samples from 887 breast cancers. The samples were taken from women 35-79 years old who participated in the Western New York Exposures and Breast Cancer Study (WEB study). Extensive in-person interviews were used to collect information on potential breast-cancer risk factors and confounding factors.

Results of the research were presented at the American Association of Cancer Research meeting held in Los Angeles in April.

"We found that hypermethylation of E-cadherin, but not of the other genes, was more likely to occur in estrogen receptor (ER)-negative than in ER-positive tumors," said Tao. ER-positive tumors are those that express receptors for the hormone estrogen. Such tumors respond to treatments that block these receptors.

"Similarly, hypermethylation of E-cadherin was more frequent among progestin receptor (PR)-negative cases," said Tao. "Compared to tumors that were both ER- and PR-positive, tumors that were both ER- and PR-negative were more likely to be E-cadherin hypermethylated.

"However, hypermethylation of E-cadherin, p16 and RAR-2 was not associated with other clinicopathological features of breast cancer, such as tumor size, histological grade or nuclear grade.

"Our data suggested that promoter hypermethylation is common in breast cancer," Tao added. "Because promoter hypermethylation is potentially reversible, identifying cancers with different hypermethylation may have important consequences for breast-cancer treatment."

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HT has benefits for connective tissue, skin, joints and intervertebral disks. HT may reduce the risk of colon cancer. HT initiated around the time of menopause or by younger postmenopausal women is associated with a reduced risk of Alzheimer's disease.

Studies on the risks of postmenopausal hormone use have mainly focused on breast and endometrial cancer, venous thromboembolism (pulmonary embolism or deep vein thrombosis), stroke and coronary events.

The incidence of breast cancer varies in different countries. Therefore, currently available data cannot necessarily be generalized. The degree of association between breast cancer and postmenopausal HT remains controversial.

Women should be reassured that the possible risk of breast cancer associated with HT is small (less than 0.1% per annum). For combined HT, observational data from the Million Women Study suggested that breast cancer risk was increased as early as the first year, raising serious reservations on possible methodologic flaws. On the contrary, randomized controlled data from the Women's Health Initiative (WHI) study indicate that no increased risk is observed in women initiating HT, for up to 7 years. It should be noted that the majority of subjects in the WHI study were overweight or obese.

Data from the WHI and Nurses Health Study suggest that long-term estrogen-only administration for 7 and 15 years, respectively, does not increase the risk of breast cancer in American women. Recent European observational studies suggest that risk may increase after 5 years.

There are insufficient data to evaluate the possible differences in the incidence of breast cancer using different types and routes of estrogen, natural progesterone and progestogens, and androgen administration. Baseline mammographic density correlates with breast cancer risk. This does not necessarily apply to the increase in mammographic density induced by HT.

The combined estrogenprogestogen therapy-related increase in mammographic density may impede the diagnostic interpretation of mammograms.

Unopposed estrogen administration induces a dose-related stimulation of the endometrium. Women with a uterus should have progestogen supplementation.

Continuous combined estrogenprogestogen regimens are associated with a lower incidence of endometrial hyperplasia and cancer than occurs in the normal population.

Direct intrauterine delivery systems may have advantages. Regimens containing low-/ultra-low-dose estrogen and progestogen cause less endometrial stimulation and less bleeding.

The HT-related risk for serious venous thromboembolic events increases with age (although .minimal until age 60), and is also positively associated with obesity and thrombophilia. By avoiding first-pass hepatic metabolism, transdermal estrogen may avert the risk associated with oral HT. The impact on the risk of a thromboembolic event may also be affected by progestogen, depending on the type. Late starters of standard-dose HT may have a transient slightly increased risk for coronary events. The risk of stroke is correlated with age. HT may increase the risk of stroke after the age of 60.

Safety data from studies of low-dose and ultra-low-dose regimens of estrogen and progestogen are encouraging.

The efficacy and safety of complementary alternative medicines have not been demonstrated and further studies are required.

Selective serotonin reuptake inhibitors, selective noradrenaline reuptake inhibitors and gabapentin are effective in reducing vasomotor symptoms in short-term studies. Their long-term safety needs further evaluation.

There are no medical or scientific reasons to recommend unregistered bioidentical hormones. The measurement of hormone levels in the saliva is not clinically useful. These customized hormonal preparations have not been tested in studies and their purity and risks are unknown.

There is urgent need for further research especially into the relative merits of lower doses, regimens and routes of administration.

The safety of HT largely depends on age. Women younger than 60 years old should not be concerned about the safety profile of HT. New data and re-analyses of older studies by women's age show that, for most women, the potential benefits of hormone therapy given for a clear indication are many and the risks are few when initiated within a few years of menopause. In view of the new data, Regulatory Authorities should review their current recommendations as a priority.

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