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REPRINT:The Role of Nitric Oxide and Arginine in the Normal and Tumorous Breast Carol L. MacLeod, Ph.D. |
The discovery that the simple gas nitric oxide has important and quite remarkable biological properties electrified the scientific community in the late 1980s. This discovery was awarded the Nobel Prize in Physiology and Medicine in 1998 because of the importance of this substance in controlling blood pressure, regulating nervous system functions and in immune responses. However, the effect of this natural bioactive substance on breast development and breast cancer requires further study in a reliable model system because numerous conflicting studies leave unsettled whether nitric oxide stimulates or inhibits tumor growth and spread (metastasis). Our genetic breast cancer model system has already permitted an answer to part of this question: nitric oxide stimulates tumor growth and the number of tumors that form. It-is now important to determine precisely which cells are producing the damaging nitric oxide that causes this unexpected effect. This is important since nitric oxide is made by all the cells in the breast: (1) in special immune cells that migrate into tumors, (2) in the special cells of the breast designed to produce milk (epithelial); those epithelial cells are the ones that cause breast cancers and, (3) in the fatty cells and "scaffolding cells" that surround, support and nourish the breast epithelial cells (the fat pad). To do this, we will transplant young breast epithelial cells that are genetically programmed to later become tumor cells into a fat pad surgically cleared of epithelial cells. These will either have or lack the ability to make nitric oxide. From our experiments, we will determine the cell types that are producing the damaging nitric oxide.
Our lab also found that when a dietary component of protein (arginine, that is needed for the synthesis of nitric oxide) is removed from the diet of mice, the rate of breast tumor growth and metastasis is significantly reduced. For this reason, studies are proposed to assess the consequences of genetically removing a cellular gateway that permits arginine to enter cells. Without this gateway, we recently discovered immune cells are unable to make nitric oxide. If those cells are important sources of nitric oxide that cause the rapid growth of the breast cancer cells and permit their escape to spread to other body sites, then blocking that gateway might reduce tumor growth and metastasis. Hence, the second aim of our study is to determine if removing that gateway for arginine reduces the rate of breast cancer growth and metastasis.
The results of our studies will provide important leads regarding diet changes that might be beneficial to women and what substances might inhibit nitric oxide. Our findings will prepare the foundation for a further study of women who are at risk for breast cancer relapse. The breast cancer mouse model provides a genetic approach to test directly and conclusively the function arginine transport on nitric oxide formation in breast cancer development and metastasis. It will also determine if the gateway for arginine entry into cells is a good target for the development of new therapeutics. In fact there are several practical reasons to elucidate the specific role of NO in breast cancer. Dietary restriction of L-arginine is known to reduce circulating arginine levels and can improve clinical outcome in a variety of conditions. The identification of the precise arginine gateway involved in NO production may provide new opportunities for therapeutic intervention.
Final Report (2001)
The breast cells responsible for milk production, called epithelial cells, and are the major culprits in breast cancer. The excessive and invasive growth of these cells leads to the development of cancer. However, excessive growth alone is not cancer and further, it occurs quite frequently. During the menstrual cycle and in pregnancy, these cells cyclically proliferate and regress and sometimes grow too much. This sometimes results in small or large breast lumps. Their presence is associated with breast cancer. Our research systematically investigated the biology and genetics of these cells with the long range purpose of finding the signature of those that are truly pre malignant and the lesions that are not likely to cause a problem for the women who have them.
We were able to establish and validates useful model to systematically assess the influence of specific gene in the progression of normal cells to those that grow excessively, but are not dangerous, to some that later become malignant cancer cells. We conducted biological tests to determine the properties of these cells with the longer range goal of validating the model so we can assess the potential of each of these types of cells within the array of host factors (those things that are found inside our own bodies) that contribute to the development of malignancy.
The funding we received from BCRP led to the recent award of a new grant to investigate the potential of this model in a prevention setting. This new award would not have been possible without BCRP funding of the initial stages. Now we are in a position to learn if the model will be useful to test new prevention measures. We are currently testing a substance derived from Soy Beans that might have activity to halt the early changes in pre-malignancy.
Our work led to the publication of a paper in Cancer Research in 2001.
Publications:
1. Nicholson B, Manner C, Kleeman J, MacLeod CL. Sustained nitric oxide production in macrophaes requires the L-arginine transporter, CAT2. J. Biol. Chem. 2001 276(19):15881-5.
2. Soler C, Valdes R, Manteiga J-G, Casado FJ, Modolell M, Nicholson B MacLeod CL, Felipe A, Celada A, Pastor-Anglada M. Lipopolysaccharide (LPS)-induced apoptosis of macrophages determines the up-regulation of concentrative nucleoside transporters CNT1 and CNT2 through TNF-alpha-dependent and -independent mechanisms. J. Biol. Chem. 2001 276(32):30043-9.
3. Maglione JE, Moghanaki D, Young LJT, Manner CK, Ellies LG, Joseph SO, Nicholson B, Cardiff RD, MacLeod CL. Transgenic polyoma middle-T mice model premalignant mammary disease. Cancer Res. 2001 61:8298-305.
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