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DERT Papers of the Month

By Jerry Phelps
February 2007

Predictive Gene Also Maintains Differentiation of Mammary Ductal Cells

A gene known as GATA-3 is in a family of genes responsible for driving the processes that take stem cells down the path of differentiation that lead to mature cells regardless of their ultimate fate. NIEHS-supported researchers at the University of California San Francisco have now determined that GATA-3 is also required for the maintenance of differentiation in ductal cells of the mammary gland.

Cancer researchers know that breast tumors with high GATA-3 expression have a good prognosis. The cancers tend to be well-differentiated, and the cells maintain many characteristics of normal mammary cells including high numbers of estrogen receptors. In contrast, cancers with low expression of the gene tend to be diffuse and poorly differentiated and lead to poor prognosis for the patient. The new research offers clues to why this is so.

Mammary ductal cells, also known as luminal cells, line the mammary ducts that carry milk during lactation. They are a primary site in the mammary gland for cancers to form. The research suggests that the loss of functioning genes and the subsequent failure to maintain the mature state of the cells is what leads to the loss of differentiation and uncontrollable proliferation during cancer progression.

The new finding suggests that the gene may play a key role in the development of breast cancer and possibly other malignancies.

Citation: Kouros-Mehr H, Slorach EM, Sternlicht MD, Werb Z. 2006. GATA-3 maintains the differentiation of the luminal cell fate in the mammary gland. Cell 127(5):1041-1055.

Effects of Low-level Arsenic on Hormone Activity

Arsenic is known to be acutely toxic at moderate to high doses and to cause a wide variety of adverse health outcomes at relatively low doses. New research findings from the NIEHS Superfund Basic Research Program-supported laboratory of Josh Hamilton at Dartmouth Medical School shed light on a possible mechanism by which arsenic may produce its varied effects.

Previous research by this lab showed that arsenic disrupted glucocorticoid receptor mediated gene transcription in a biphasic manner: at drinking water levels near the current EPA standard (5-50 parts per billion) arsenic enhanced the hormone-stimulated gene expression, but at slightly higher doses (50-200 parts per billion) it almost completely blocked hormone-stimulated receptor gene expression. The new research findings demonstrated the same effects with progesterone, a steroid hormone involved in female reproduction, and mineralocorticoid hormone, a steroid hormone responsible for salt and water metabolism and balance.

This study determined that arsenic, unlike most endocrine disruptors, does not activate the receptors by mimicking the natural hormone, nor does it block the natural hormone from binding to and activating its specific receptor. The investigators also found that arsenic does not inhibit the movement of the hormone-activated receptor into the nucleus of the cell to bind to DNA and initiate gene expression.

Citation: Bodwell JE, Gosse JA, Nomikos AP, Hamilton JW. 2006. Arsenic disruption of steroid receptor gene activation: Complex dose-response effects are shared by several steroid receptors. Chem Res Toxicol 19(12):1619-1629.

Epoxide Hydrolase Inhibitors Effective for Cardiac Hypertrophy in Mice

Cardiac hypertrophy is defined as a thickening the of the heart muscle often as a result of high blood pressure. The heart muscle grows larger to compensate for the added stress of pumping blood against the increased pressure. Over time this condition can result in a weakening of the heart and can lead to congestive heart failure. New research supported by NIEHS in the laboratory of Bruce Hammock at the University of California Davis sheds light on a possible treatment to prevent heart enlargement.

Previous work by Hammock and his collaborators demonstrated that inhibition of an enzyme called epoxide hydrolase lowered blood pressure and lessened kidney damage in a laboratory animal model. The new research findings show that epoxide hydrolase inhibitors block an immune system protein, known as NF-κB, which plays a role in cardiac hypertrophy and accompanying arrhythmia. The inhibitors were effective in preventing and reversing cardiac hypertrophy in a mouse model.

These findings show that by blocking the pathway leading to the overgrowth of cardiac muscle, preventing the progressive deterioration of heart function is possible. This work could lead to new therapies for treating enlarged hearts and heart arrhythmias-conditions that currently require more invasive treatment options and ultimately progress to heart failure and sudden cardiac death.

Citation: Xu D, Li N, He Y, Timofeyev V, Lu L, Tsai HJ, Kim IH, Tuteja D, Mateo RK, Singapuri A, Davis BB, Low R, Hammock BD, Chiamvimonvat N. 2006. Prevention and reversal of cardiac hypertrophy by soluble epoxide hydrolase inhibitors. Proc Natl Acad Sci U S A 103(49):18733-18738.

Identification of CRP Variants and Association with Serum Levels

C-reactive protein (CRP) is a marker for inflammatory processes. More recent research demonstrates that an elevated CRP level is also a risk factor for diabetes, hypertension and cardiovascular disease, and that genetic variation within the gene coding for the protein may be associated with levels circulating in the blood stream. A new study from the University of Washington partially supported by NIEHS confirms that genetic variations in the gene for CRP are associated with increased serum levels in the general population.

The study participants were part of the National Health and Nutrition Examination Survey (NHANES). DNA analyses were conducted on 7,159 participants. Genotyping was performed on all samples for nine single nucleotide polymorphisms previously found in the CRP gene. Several of the genetic variations for increased and decreased CRP levels were more or less prevalent in different racial groups making up the study participants.

These findings are important because they confirm that serum levels of CRP are genetically influenced. The genetic variations identified in this study could be used to identify people at risk for cardiovascular and other serious diseases or to target people for more aggressive interventions to prevent heart disease from occurring.

Citation: Crawford DC, Sanders CL, Qin X, Smith JD, Shephard C, Wong M, Witrak L, Rieder MJ, Nickerson DA. 2006. Genetic variation is associated with C-reactive protein levels in the Third National Health and Nutrition Examination Survey. Circulation 114(23):2458-2465.

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