Biology of the Normal Breast: The Starting Point
Although much research has been done on the biology of breast tumors; we still know very little about the structure and biochemistry of the normal breast. BCRP has made studying normal breast biology a priority in hopes that we will be able to sort out early steps that occur before actual tumors form.
Research Conclusions
All grants in this priority issue are still underway.
Research In Progress
All of the projects investigating normal breast biology were underway this year, and several have made significant progress. One group of studies is investigating the influence of hormones and growth factors on breast development. Mary Helen Barcellos—Hoff, Ph.D. of Lawrence Berkeley National Laboratories has begun studies to determine how the activity of a particular protein called TGF—beta (Transforming Growth Factor—beta) is regulated in different parts of the breast during the different stages of development. The growth and development of particular parts of the breast ductal system (endbuds and lobulo—alveolar structures) are controlled by the hormones estrogen and progesterone. She found that TGF—beta was activated during the growth of these parts of the breast ductal system. Through studies in which mice were treated with hormones, she was able to provide the first evidence that TGF—beta produced in the breast inhibits certain aspects of breast development and that TGF—beta biological activity is under hormone regulation through its precursor. Satyabrata Nandi, Ph.D. from the University of California, Berkeley is continuing a project to find breast cancer—related genes associated with pregnancy. It is recognized that full—term pregnancy in young women offers a lifetime protective effect of about 30% for later developing breast cancer. Dr. Nandi uses a rat model system and has identified a novel gene, called RMT1, that appears to be present in high amounts in the breast cells of virgin rats. The virgin rats are more susceptible than parous (already having completed pregnancy and birth) rats to chemical carcinogens. The rationale and background for this project were recently published in the Proceedings of the National Academy of Sciences, USA (Mar 2, 1999; 96(5): 2520—5).
Some investigations are looking into factors that influence whether cells behave like cancer cells. Gary Bokoch, Ph.D. of The Scripps Research Institute is continuing his investigation into the connection between growth factors and cell death. He has found that certain enzymes called PAKs have the ability to suppress the cell death that normally occurs when certain growth factors are removed. This is a new mechanism that may explain one way that breast cancer cells avoid dying. Dr. Bokoch has also found that PAK acts on a molecule that regulates the ability of cells to contract, a function critical to cell movement and tumor metastasis. He is investigating how this PAK target, as well as others, contribute to cell motility. Vito Quaranta, M.D., also of The Scripps Research Institute, is finding that cell motility can be regulated when a particular component of the cellular matrix, Laminin—5, is cut by a specific enzyme, MMP—2. This discovery could ultimately lead to a new therapeutic target for treating breast cancer metastasis.
Other researchers are investigating factors that have ultimate chemopreventative implications for breast cancer. Xiao—kun Zhang, Ph.D. of The Burnham Institute is continuing to characterize the biological effects of different types of retinoids (Vitamin A) on breast cancer cells. His findings have uncovered a molecular basis for the ability of a retinoid acid receptor (RAR—beta) to induce cell death in breast cancer cells. Nicholas Rampino, Ph.D., also of The Burnham Institute, is investigating the influence of different estrogen—blocking agents (anti—estrogens) on protecting breast and endometrial cells from damage caused by oxygen. He is finding that after exposure to oxygen, estrogen—sensitive cells treated with raloxifene show lower mutation rates, less DNA damage and less interference with the cell cycle, as compared to those treated with tamoxifen or the pure anti—estrogen ICI 182,780. This finding could provide a basis for optimizing chemoprevention of breast cancer.
Recently Initiated Research
In previous years the Normal Breast Biology Priority Issue could only be addressed by large projects run by established investigators. In 1999 (Cycle V), we offered postdoctoral, new investigator and IDEA awards in this priority issue and awarded seven grants.
Two postdoctoral fellows are searching for as yet unidentified genes involved in normal cell behavior that could prove to be critical sites for mutations in cancer cells. Jarnail Singh, Ph.D. of The California Pacific Medical Research Institute is searching for genes that act as intermediates for the Id–1 gene in influencing cell movement and Hong Zhang, Ph.D. of Stanford University is searching for genes responsible for causing cells to stop dividing (senesce).
Two investigators are determining whether genes that regulate the growth and physiology of normal cells in non–human species, or tissues other than breast, are functional in the breast. Peter Jackson, Ph.D. at Stanford University is studying POP genes, which when mutated cause yeast to make abnormal amounts of DNA. He is determining whether the POP genes are playing a similar role in the breast. If they are, mutations in these genes could be the basis for oncogene amplification (an early step in the development of cancer) in breast tumors. Carmen Hagios, Ph.D. of Lawrence Berkeley National Laboratory is undertaking a postdoctoral fellowship to investigate the role of two embryonic genes, HOXa–1 and HOXb–7, in normal breast. She will determine whether they are factors in breast development and whether deregulation of these genes leads to tumor formation.
Two investigators are defining the role in the normal breast of cellular factors that have already been correlated with tumor formation, with the ultimate goal of determining whether the factors can be exploited for breast cancer treatment, detection, or prevention. Wen Xie, M.D., Ph.D. of The Salk Institute for Biological Studies is using transgenic mice in her postdoctoral fellowship to characterize the effect of extra ACTR/AIB1, a mediator of estrogen action, on normal breast development and susceptibility to cancer. Nitric oxide stimulates breast tumor development, but there are several conflicting theories about how it is achieving its effect. Carol MacLeod, Ph.D. of the University of California, San Diego is using transgenic mouse models to investigate the effect of removing nitric oxide on the normal breast, the immune system and tumor development.
Finally, Sheldon Miller, Ph.D. of the University of California, Berkeley will study the secretory process of the breast. The basic function of the breast is to produce milk, which involves the transport of water across the epithelial cells and into the breast ducts. This essential process of breast biology is poorly understood. Moreover, there is a condition called gross cystic disease, which involves the abnormal accumulation of water in the breast ducts. Women with this condition have an increased risk of developing breast cancer when compared to the general population. Dr. Miller's investigation will provide insight into this condition.
