Biology of the Normal Breast: The Starting Point
there is a critical, but often overlooked requirement for unraveling the events that lead to breast cancer development—understanding the normal structures and processes of the breast. It is paradoxical that we expend enormous efforts to learn about the biology of breast tumors, but know very little about how the normal breast is structured; how the different cell types contribute to the functioning of the breast; and how to distinguish unusual but normal structures from those whose presence indicates cancer. CBCRP identified understanding the biology of the normal breast as an area of research that needs to be emphasized and has funded research investigating this topic for the past two years.
Conclusions
The question of what role environmental factors are playing in breast cancer development has been particularly difficult to answer. Essam Enan, Ph.D., at the University of California, Davis, finished his project investigating the cellular mechanisms triggered by organochlorine pesticides in breast cancer cells. Most investigators are examining the actions of organochlorine pesticides through their association with the estrogen receptor. Dr. Enan finds that the lindane-like chemical b-HCH and the DDT-like chemical, o,p-DDT can stimulate the proliferation of breast cell lines through a mechanism that does not involve the estrogen receptor. b-HCH regulates several proteins differently in estrogen receptor-positive compared to estrogen receptor-negative cells. Most of these proteins are characterized as second messengers because they carry signals from the cell membrane to the nucleus. The second messengers regulated by b-HCH include cAMP, Src kinase, Protein Kinase A. Additionally, the tumor suppression protein p53 is differentially regulated in the estrogen receptor-positive and negative breast cell lines. This investigation has identified up new ways that for orga-nochlorine pesticides' can affect breast cancer growth.
Research in Progress
Research in progress in this areais exploring several aspects of breast cells as they relate to tumors, looking at the basic mechanisms that could explain why both normal and cancerous breast cells respond to therapeutic and preventative interventions the way that they do. Xiao-kun Zhang, Ph.D., of The Burnham Institute, is investigating the biological basis for retinoid action in breast cancer. He is investigating the cellular suicide and maturation triggers that known and newly developed retinoids have on breast cells. He finds that the pathways employed by different retinoids synergize to produce a greater growth inhibitory effect at lower doses.
The response of breast cells to normal intracellular and extracellular signals may indicate how tumor characteristics develop. Many breast tumors, which are resistant to cell death, are also better able to move to distant sites in the body. Gary Bokoch, Ph.D., of The Scripps Research Institute, is looking at how a cell growth regulating protein called p21-activated kinase (PAK) is involved in breast cell death and motility. Nicholas Rampino, Ph.D., of , has begun an investigation into the degree of DNA damage and mutation that occurs in dividing breast cells due to their exposure to estrogens and antiestrogens.
This year the CBCRP funded three RFA projects to increase our understanding of the normal breast. Two of the grants investigate the physiological changes that occur during the normal progression of the breast through puberty and pregnancy. Satyabrata Nandi, Ph.D., at the University of California, Berkeley, will investigate why the mammary glands in rats that have never had offspring are more susceptible to carcinogens than the glands in rats that have (there is a similar pattern in humans) by comparing the genes that are turned on in each type of gland. Mary Barcellos-Hoff, Ph.D., at the Lawrence Berkeley National Laboratory, will determine whether a growth factor called TGF-b has a significant role in the development of the breast. TGF-b may be important in this process because 1) it is associated with epithelial cell death, which is a necessary step in the maturation of the gland and 2) it is regulated by estrogen and progesterone at different points of breast development. Understanding the role of TGF-b in breast development could lead to finding new ways to stop tumor epithelial cells from growing. Vito Quaranta, M.D., at the Scripps Research Institute, will determine whether the processing of a component of the extracellular matrix, Ln-5, has a significant effect on the structural integrity of the breast ducts. Loss of structural integrity is believed to be the first stage in tumor cell metastasis. These studies are designed to demonstrate how developing a deeper understanding of the properties of the normal breast can give us insights into how tumors escape their normal constraints.
