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Molecular biomarkers form molecular basis for cancer prevention risk-limiting strategies

American Association For Cancer Research (AACR) : 31 October, 2005  (Technical Article)
Useful biomarkers to help prevent, diagnose and monitor treatment for cancer must share two essential characteristics: they must be consistently reliable, and they must display significant difference in expression between normal tissue and the various stages of cancer progression.
One of the goals for cancer prevention is to identify, as early as possible, molecular changes in the body that signal the onset of disease. Such 'biomarkers' may be isolated from subtle biological changes in an individual's cells, proteins or genetic makeup.

Useful biomarkers to help prevent, diagnose and monitor treatment for cancer must share two essential characteristics: they must be consistently reliable, and they must display significant difference in expression between normal tissue and the various stages of cancer progression.

Three studies presented at the 2005 American Association for Cancer Research Frontiers in Cancer Prevention Research meeting in Baltimore discuss molecules that scientists have identified as markers for skin, endometrial or breast cancer. The results suggest how these biomarkers may help monitor early onset malignancies that can be prevented from advancing to life-threatening conditions.

Blood levels of C-reactive proteins indicative of increased risk for endometrial, colorectal cancers (Abstract # 3701)

People with elevated concentrations of a protein associated with chronic low-grade inflammation are at higher risk for developing endometrial cancer, according to a new study.

C-reactive protein is a highly sensitive indicator of inflammation, and is associated with diabetes, metabolic syndrome and hyperandrogenic states. The protein is made by liver cells in response to several pro-inflammation signaling molecules known as cytokines.

In a three-part study including more than 35,000 women, C-reactive protein levels were higher in the circulation of women who developed endometrial cancer compared to blood levels of women who remained free from endometrial cancer. The risk for women who averaged 2.44 mg C-reactive protein per liter of blood was twice that of women whose blood contained an average of 1.8 mg per liter of the inflammation related biomarker.

'This is the first prospective study to report on the association between C-reactive protein, a non-specific marker for chronic inflammation, and endometrial cancer,' said Dana K. Christo, MPH, from the Johns Hopkins University School of Public Health and the study's lead author. Also participating in the study were scientists from the Fox Chase Cancer Center and the National Cancer Institute.

'This finding gives us a clue that inflammation is associated with progression to endometrial cancer, but it should be confirmed in other studies,' said Christo. 'However, our results suggest that other known risk factors, such as obesity, may lead to cancer through inflammation, which should be amenable to prevention strategies.'

P53, Polyamine Levels Rise in Sun-Damaged Skin of Individuals Harboring AK
(Abstract # 3670)

People with actinic keratosis due to exposure to the sun had increased levels of two biomarkers associated with AK lesions of the skin, according to studies conducted by researchers from the University of Arizona Cancer Center.

'Actinic keratosis is a very common lesion in aging, sun-exposed populations,' said Janine Einspahr, Ph.D., research assistant professor at the University of Arizona and lead author of the study. 'AK is much more common than the malignant condition of squamous cell carcinomas.'

SCC account for about 20 percent of skin cancers, and are non-melanoma malignancies stemming from a type of skin cells called keratinocytes.

'Since AK are precursor lesions of SCC they represent a good model of early progression in UVB-induced skin cancer, and a good model for the dissection of the molecular alterations that take place in this SCC progression,' Einspahr said.

Examining biopsies from the forearms of 789 people with sun damage, 33 people with AK, and 32 people who had previously had SCCs surgically removed, the Arizona researchers determined that individuals with AK had increased p53 levels, putricine and spermadine compared to those with sun-damaged skin.

The University of Arizona studies show that p53 expression and polyamine content in skin forearm biopsies are reliable measures over time in sun-damaged skin.

'Specific genetic alterations, such as mutation or overexpression of p53, and phenotypic, biochemical characteristics of AKs, cell proliferation/PCNA/polyamines, can be used to demonstrate the effect of chemopreventive agents. Identification of these biomarkers in even earlier stages of progression would allow targeting of populations at an even lower risk for preventive strategies,' said Einspahr.

By identifying biomarkers that consistently and accurately predict progression of skin conditions toward malignant states, Einspahr and her colleagues have established assays that can be effective in detecting precancerous conditions.

'Clinical trials to assess cancer incidence require large sample-sizes, long follow-up, and are very costly,' Einspahr said. 'Useful biomarkers could circumvent this with smaller sample sizes and studies of shorter duration.'

The Arizona cancer researchers examined biomarkers that include specific genetic alterations (mutation or overexpression of p53) and phenotypic and biochemical characteristics of AKs, (cell proliferation, PCNA, and polyamines).

PCNA is a cell cycle related protein expressed in the nucleus of cells that are in the proliferative growth phase. Polyamines are ubiquitous polycations that are essential for normal cellular proliferation and differentiation. Putrescine is the first polyamine in the pathway, spermidine the second and spermine the last. PCNA and polyamines are required for normal epidermal homeostasis but, when dysregulated, represent tissues undergoing increased cell growth and division such as in neoplasm or early cancer progression.

Italian Research Suggests Enhanced Safety in Low Doses of Tamoxifen with HRT Use (Abstract # 3456)

Early indications from the HOT Trial suggest that women can safely take a combination of hormone replacement therapy and tamoxifen at reduced dosages. Analysis of the Italian Tamoxifen Chemoprevention Trial showed a reduction of breast cancer among women who were under continuous HRT and tamoxifen in contrast to those who received HRT and a placebo.

'Tamoxifen at reduced dosages retained its antiproliferative effect,' said Bernardo Bonanni, M.D., Condirettore, Divisione di Farmacoprevenzione, Istituto Europeo di Oncologia.

'The combination was particularly effective when the HRT was administered transdermally, either with a patch or gel, and the dose of tamoxifen was reduced to 5 mg/day.' Bonanni noted that the reduced tamoxifen level was just a quarter of the dose administered in the WHI studies.

'The differences we are seeing in the HOT study may be due to the very different subject characteristics, different route of taking the medication, as well as the reduced dosage regiment administered in this more recent study,' Bonanni said.

The HOT Trial is an ongoing Phase III trial that examines a series of biomarkers in women on HRT and tamoxifen. Among the markers of interest are changes in plasma levels of the growth factor IGF-I, as well as the growth factor's binding protein, IGFBP-3, lipids, C-reactive protein, homocysteine and other biomarkers.

The study includes 210 HRT users who receive either 1 or 5 mg/day, or 10 mg/week doses of tamoxfen. The control arm of the study includes HRT users who also take a placebo. Low doses of tamoxifen in combination with the HRT result in significantly modulated levels of biomarkers of breast carcinogenesis and cardiovascular risk among women taking HRT.
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