By David N. Leff
Virginity, whether in a young girl experiencing puberty, or in a sexually abstinent adult woman, shows up in the mammary glands. These lactiferous structures wax and wane, something like the tides, as they meet the changing milk-making needs of pregnancy, lactation and weaning.
Molecular biologist Chu-Xia Deng heads a team at the National Institutes of Health (NIH) that has engineered a strain of mouse that faithfully mimics the cycle of human mammary gland development. ¿In virgin mice,¿ he told BioWorld Today, ¿their mammary gland tissue displays a tree-like structure, with a stem and many small branches. But virgin mice do not have a single leaf.
¿Once they are pregnant,¿ he went on, ¿under the influence of hormones, they come to develop an alveoli-like structure. Now you may think of them in the springtime as a small branch covered with leaves. It reaches the highest peak at lactation, because those mammary ducts are fully developed and producing milk to give to their babies. In the next stage, weaning the baby, apoptosis shrinks them back nearly to the virgin state. As that wintertime comes, the wind blows away the leaves and small branches, leaving only the main stem.
¿In those mice,¿ Deng said, ¿we would like to understand how the mutated BRCA1 gene causes breast cancer in humans.¿
Discovery of that long-sought mutant gene for familial mammary cancer made media news five years ago. (See BioWorld Today, Sept. 15, 16 and 19, 1994, all p. 1.)
Breast cancer is the second leading cause of cancer death in women. It will strike one in nine women. This year, an estimated 175,000 women in the U.S. will receive a diagnosis of mammary carcinoma, and about 43,000 will die. Mutations in the BRCA1 gene are found in 90 percent of women who have inherited both breast and ovarian cancer, and in 50 percent of those with familial breast cancer alone.
Finding that tumor-associated gene was a giant step toward coming to grips with the disease, but only one step in a long journey. Hindering its progress toward effective diagnosis and efficacious treatment was the lack of a true-to-human animal model. That step is reported in the May 1999 issue of Nature Genetics, under the title: ¿Conditional mutations of Brca1 in mammary epithelial cells results in blunted ductal morphogenesis and tumor formation.¿ Deng, its senior author, heads the laboratory of mammalian genetics at the Development and Disease Branch of NIDDKD ¿ the National Institute of Diabetes, Digestive and Kidney Diseases, at the NIH in Bethesda, Md.
His article describes the creation and performance of that breast cancer mouse pinch-hitter. ¿This model,¿ said NIDDKD¿s scientific director, Allen Spiegel, ¿is the first that shows cancer development similar to the development of breast cancer in women. It will be an important tool for future work on tumors and their progression.¿
Deng had striking confirmation of that similarity between model and human early in March, when he attended a small meeting in Annapolis, Md. ¿There,¿ he recounted, ¿I showed a few microscope slides of mammary gland tumors in our knockout mice to human histopathologist Barry Gusterson, at the [British] Institute of Cancer Research.
¿Barry got excited,¿ Deng recalled. ¿He told me he couldn¿t distinguish them from the human tumor. They showed a strong tumor reaction, and a border between the tumor tissue and the normal tissue suggested they were highly invasive. He told me they were very similar to the human BRCA1 carcinoma.¿
That mouse model revealed a hitherto unknown pathway leading from a healthy caretaker BRCA1 tumor repressor to a tumorigenic array of genes presided over by the sinister mutant p53 oncogene.
¿When we knocked out the BRCA1 gene only,¿ Deng recounted, ¿our model tumor developed at quite a low frequency over a long period of time. What it tells us is that BRCA1 of itself in a patient may not cause a tumor. It has to get some other guy ¿ some other gene. Because the BRCA1 is important for maintaining genetic stability. In other words, it¿s a protector gene. If you lose the BRCA1, the genes under its protection become bad. They produce proliferation without any cell-cycle checkpoint.
¿If this mutation happens to mutate the p53,¿ Deng continued, ¿which is a very important tumor suppressor gene, it will allow the cell to grow, to become a tumor.
¿To prove this hypothesis, we wanted to test whether the p53 will enhance or accelerate the tumor formation. So we crossed our knockout mice into p53 heterozygote mice. These animals have only one functional copy of p53. The other copy has already been mutated. And compared with the wild type, which have two copies of p53, the tumor cell only needed to mutate one copy to grow up fast. So we did see acceleration of the tumor formation, suggesting that the p53 mutation is required for the tumor cell to grow, and its growth timing shortened.¿
Deng¿s paper in Nature Genetics concludes that those mice should ¿serve as a model to study genetic pathways dysregulated in human hereditary breast cancer, and facilitate therapeutical and chemoprevention studies.¿
Exciting¿ Therapeutic Peptide In The Works
However, he told BioWorld Today, ¿We do not see any cure in a shorter time. Based on our findings, there is perhaps a long way to go. To cure the BRCA1-related tumor, we have to be able to stabilize the genome. Because when we lose that gene¿s protective function, it destabilizes it.
¿Now we¿re trying to search for the downstream gene targets of BRCA1. If we find any gene missing in this knockout mouse, we will try to supply it back. Some smaller genes are easier to supply back, so we can do that. And our hope is that perhaps BRCA1 activated some other gene. Then we can perhaps develop an inhibitor to inhibit this activity of other genes, and perhaps stabilize the genome.
¿Another aspect we want to do is use these mice to try to develop drugs specific to the mammary gland. There are some compounds now that are quite efficient ¿ tamoxifen, adriamycin ¿ but those drugs also have side effects toxic to other organs. We can try to use our mouse model to target compounds to the mammary gland and look at their effects. We are now beginning to search for such a peptide,¿ Deng concluded, ¿and getting some quite exciting data.¿ n