Study in Cancer Research used mice with one copy of p53 silenced and ER gene expression doubled.

Minor alterations in p53 and estrogen receptor-alpha gene expression appear to play a role in triggering molecular changes that lead to breast cancer, according to researchers at Georgetown Lombardi Comprehensive Cancer Center. The results suggest that the two genes are involved at the inception of breast cancer development, rather than just its progression, claim the study’s two authors, Priscilla A. Furth, M.D., professor of oncology and medicine, and Edgar Dia-Cruz, Ph.D., Lombardi fellow. The results are published in Cancer Research.

Dr. Furth’s team has developed mouse models in which genes can be manipulated to investigate the development and progression of breast cancer. One of the laboratory’s aims is to develop a panel of genetic tests that could help predict the likelihood of developing breast cancer.

Alterations in p53 are reported in some 30–40% of women with breast cancer, and about 70% of breast cancer patients have estrogen receptor-positive disease, report Drs. Furth and Dia-Cruz. To investigate the role of p53 and estrogen receptor gene expression on breast cancer preneoplasia, the researchers generated mice in which one copy of p53 was silenced and estrogen-receptor gene expression was increased twofold.

Both mouse models subsequently developed precancerous changes in their breast tissue. Animals harboring only a single p53 gene and with twice the level of estrogen-receptor expression demonstrated even more pronounced evidence of early-stage breast cancer progression. “Normal breast tissue functioning requires a balance of cell growth and cell death, and in this study we found that both deregulated estrogen receptor function and p53 expression, independently and in combination, altering this balance and transforming cells,” states Dr. Furth.

The researchers were also surprised to find that what are in effect relatively minor changes in the two genes had such an important impact on otherwise healthy breast tissue. “We increased estrogen-receptor expression but in a way that could be found in normal variation among women, and the mice lost one of their two p53 genes, but loss of that single copy only decreases but does not eliminate expression.”

Dr. Furth admits that p53 and the estrogen-receptor gene are unlikely to represent the only two genes involved in triggering breast cancer development. Nevertheless, she suggests that the new findings could help pave the way for new predictive tests for breast cancer. “These are not the only two molecules that are responsible for breast cancer development, but they are important, and they can potentially provide us with an early warning or even with prevention strategies.”

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