Genetic Alterations Can Effect Breast Cancer Risk from Low-Dose Radiation

The study, conducted by scientist from the US Department of Energy Lawrence Berkeley National Laboratory (Berkeley, CA, USA), could lead to new tools to identify women who have higher or lower risks of breast cancer from low-dose radiation. Such a predictive approach could help guide the treatment of cancer patients who may be better helped by nonradiation techniques.

The findings also back up the hypothesis that an individual’s genes play a big role in understanding her breast cancer risk from low-dose radiation. The current model for predicting cancer risk from ionizing radiation is directly proportionate to dose. But there is mounting appreciation that this linear correlation does not apply at lower doses. Instead, the health effects of low-dose radiation may considerably differ between individuals depending on their genetic makeup.

The scientists, led by Dr. Andy Wyrobek of Berkeley Lab’s life sciences division, reported their research October 19, 2012, in the journal PLOS ONE. They examined mammary tissue from two strains of mice--one that is vulnerable to radiation-induced mammary gland cancer and one that is resistant--before and after the mice were exposed to low-dose radiation.

The investigators then searched for variations between the two strains in how their genes to switch on and off. They employed a technique that scans thousands of genes simultaneously. They found differences in genes that regulate tissue stress response, DNA repair, cellular proliferation, immune response, and other cellular and tissue processes. They also discovered that these disparities carried over to surviving breast cancer in women. Breast cancer patients with gene expression profiles similar to the cancer-resistant mice (before radiation exposure) were more apt to survive eight years after diagnosis. Women with gene expression profiles similar to the cancer-sensitive mice were less likely to survive after eight years.

Based on this, the scientists believe the cellular and tissue processes that regulate the mice’s risk of mammary gland cancer from low-dose radiation are similar to the processes that affect a woman’s chance of surviving breast cancer. “Our studies of genetic differences in radiation sensitivity in mice, and individual variation in breast cancer survival in women, suggest that there are women who, because of their genes, have a higher risk of breast cancer when they’re exposed to low-dose radiation,” said Andy Wyrobek, who conducted the research with Dr. Antoine Snijders, Joe Gray, and several other Berkeley Lab scientists.

“This raises the possibility that we can use gene expression profiles to develop simple tests that screen for women who may be sensitive to low-dose radiation versus women who are resistant,” Dr. Snijders stated.

The scientists first examined the lab mice before exposing them to radiation. They identified more than 130 genes that express differently in blood and mammary tissue samples of cancer-resistant mice compared to cancer-sensitive mice. To determine if these differences also relate to humans, the scientists searched human breast cancer “knowledge bases” that tie the expression of patients’ tumor genes with their survival outcomes. They examined newly diagnosed women before they received chemotherapy or radiation. Women with gene expression levels similar to those of radiation-sensitive mice were less apt to survive after eight years. In comparison, women with expression levels similar to those of the resistant strain were more liable to survive the eight-year duration of the follow-up.

Then, gene expression analyses conducted a few hours after the end of low-dose exposure found alterations in many genes in the mammary tissue of cancer-sensitive mice. Large numbers of genes that control their immune system were suppressed, while genes that regulate pubertal mammary gland development were turned on by mistake. In cancer-resistant mice, these genes demonstrated only a small alteration in activity.

Analyses performed one month after exposure provided remarkable differences in the expression of a large collection of genes that control cell proliferation. The cancer-sensitive mice had up-regulated many genes associated with cell division and cell renewal. The cancer-resistant mice had downregulated these same genes below normal levels, which suggests they were able to activate tissue mechanisms that suppress cellular proliferation that can lead to cancer.

These disparities once more continued over to humans. Breast cancer patients whose renewal and cell division genes were upregulated, comparable to the cancer-sensitive mice that did not survive as long as patients in which the same genes were suppressed. The scientists are now engineering these gene expression signatures by studying large groups of women with breast cancer. They are also evaluating the processes by which these signatures control radiation sensitivity employing distinctive breast cell culture models developed at Berkeley Lab.

“This research opens promising opportunities for developing blood tests that predict a woman’s risk for breast cancer, and which identify women who are susceptible to the cancer effects of low-dose radiation exposures,” concluded Dr. Wyrobek.

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