© 1999 by Oxford University Press
Journal of the National Cancer Institute, Vol. 91, No. 1, 1,
January 6, 1999
© 1999 Oxford University Press
MEMORANDUM FOR: Science Writers and Editors on the Journal Press List
December 30, 1998 (EMBARGOED FOR RELEASE 4 P.M. EST January 5)
Resistance of Breast Cancer to Tamoxifen Can Be Reversed in Animals by Antibodies to Transforming Growth Factor-ß
A new study may have identified and reversed a novel mechanism that makes some breast cancers resistant to the widely used drug tamoxifen.
Carlos L. Arteaga, M.D., of the Vanderbilt University School of Medicine, and co-authors present their findings in the January 6 issue of the Journal of the National Cancer Institute.
The authors knew from previous experiments that transforming growth factor-ß (TGF-ß ) is overproduced by some human breast cancers that are resistant to tamoxifen. Therefore, they determined in this study whether interfering with the production of TGF-ß could reduce the resistance of certain human breast cancer cells to the effects of tamoxifen.
Two human breast cancer cell lines were used in this study, one (LCC1) that produced low levels of TGF-ß and responded to tamoxifen and another (LCC2) that overproduced TGF-ß 2 and was resistant to tamoxifen. Both cell lines had high levels of estrogen receptors. The authors first measured in cell culture whether interference with TGF-ß production in the LCC2 cells made them more responsive to the effects of tamoxifen and then in essence performed similar experiments on LCC1 and LCC2 tumors induced in two different types of mice.
The authors report that the response of LCC2 cells to tamoxifen was not altered in cell culture by interfering with TGF-ß secreted by the tumor cells. After LCC2 tumors were induced in nude mice, some of the mice were treated with tamoxifen alone, while others received tamoxifen and neutralizing TGF-ß antibodies. Tamoxifen alone had no effect on tumor growth, while tumor growth was arrested in those receiving the combination. The same experiment with LCC2 cells, when repeated in beige mice, did not result in any slowing of tumor growth. LCC1 tumors were statistically significantly more sensitive to tamoxifen in nude mice as contrasted to beige mice. Since beige mice lack natural killer cell function, the authors propose that immune mechanisms may be involved partially in the antitumor effect of tamoxifen and that overproduction of TGF-ß may interfere with this mechanism, thus contributing to tamoxifen resistance.
Contact: Cynthia Manley, Vanderbilt University, (615) 322-4747; fax (615) 343-3890.
Chromosome Used to Stop Growth of Breast Cancer Cells
A specific human chromosome, when introduced into cells of human breast cancer growing in the laboratory, brought most of the cancer cells to a state of permanent growth arrest.
This finding is presented by Andrew W. Cuthbert, Ph.D., of Brunel University, Uxbridge, United Kingdom, and colleagues, in the January 6 issue of the Journal of the National Cancer Institute.
When most human cells divide, the ends of their chromosomes are often imperfectly replicated, and accumulation of these end defects, perhaps in combination with other processes, leads eventually to cell death. However, most cancer cells produce an enzyme called telomerase that compensates for the end defects in chromosome replication and thus promotes cell immortality. Interfering with cellular production of telomerase may be a way to stop the unchecked growth of cancer cells.
The authors worked with cells of the human breast cancer cell line 21NT, cells that in laboratory culture grow immortally. Into these cancer cells they introduced by microcell transfer either human chromosome 3, 8, 12, or 20, obtained from normal cells. They then measured the subsequent telomerase activity in these hybrid cells, together with their growth potential.
Those cell colonies containing introduced chromosomes 8, 12, and 20 showed an undiminished growth rate and normal telomerase activity when compared with unmodified control cultures. In marked contrast, colonies into which human chromosome 3 had been introduced showed, in most cases, complete growth arrest after 10-18 population doublings. Furthermore, telomerase activity was reduced by 98% or more in all of the colonies that entered growth arrest. Around one in 11 hybrid cell lines did not appear to respond to chromosome 3 and retained telomerase and immortality. The authors were able to detect overlapping deletions in the introduced chromosome 3 in these cells, enabling them to narrow the location of the gene or genes that turn off telomerase in normal breast tissue.
The authors conclude that switching off telomerase in breast cancer cells allows them to regain the mechanism by which normal cells limit their growth. The search is now on for anti-cancer drugs that can produce the same effect.
In an editorial, Jerry W. Shay, Ph.D., of The University of Texas Southwestern Medical Center, Dallas, notes that the study by Cuthbert et al. provides further confirmation of the importance of a telomerase inhibitor on chromosome 3 and that inhibition of telomerase could provide a novel approach to treating cancer. The challenge will be to find out how to make cancer cells age and stop dividing while our healthy cells continue to divide, he says.
Contact: Professor Robert F. Newbold, Brunel University, United Kingdom, 44-1386-701176; e-mail rnewbold{at}atlas.co.uk. Editorial: Heather Stieglitz, University of Texas, (214) 648-3404; fax (214) 648-9119.
ß-Carotene Supplementation Produces Precancerous Lung Lesions in Ferrets
A new study has found that ferrets given ß -carotene supplements developed precancerous changes in lung tissue, changes that were even more pronounced in ferrets that received the supplements and were also exposed to cigarette smoke.
These findings are presented by Xiang-Dong Wang, M.D., Ph.D., Human Nutrition Research Center at Tufts University, Boston, and colleagues in the January 6 issue of the Journal of the National Cancer Institute.
This work was prompted by a seeming contradiction, in that people who eat more fruits and vegetables have high levels of serum ß -carotene and a lower risk of lung cancer, yet two studies using ß -carotene supplements showed an increase in lung cancer among smokers and asbestos workers. Therefore, the authors studied the ferret, which absorbs and metabolizes ß -carotene much as in humans and has also been used to study tobacco smoking and inhalation toxicology. Four groups of six ferrets each were divided as follows: controls, who received the unsupplemented diet that contained the equivalent in human terms of 2.3 mg per day of ß -carotene; an unsupplemented group that was exposed to cigarette smoke daily for 6 months; a supplemented group that received the human equivalent of 30 mg per day of ß -carotene; and a fourth group that was both supplemented with ß -carotene and exposed to cigarette smoke. After 6 months, ß -carotene concentrations were measured in the plasma and in lung tissues, and both cellular changes and changes in the expression of various genes were measured in lung tissues.
Precancerous tissue changes were found in the lung tissues of ß -carotene-supplemented animals, and this response was enhanced by exposure to tobacco smoke. Compared with the control group, all other animals had lower concentrations of retinoic acid (an active form of vitamin A that is protective against cancer) in lung tissue, which may be explained by alterations in certain gene expressions found in these tissues.
The authors propose that smoking fosters breakdown products of supplemental ß - carotene that differ from the breakdown products of carotenoid-rich natural diets and that these products of ß -carotene metabolism can promote the formation of precancerous changes in lung tissue.
Editorial writer Reuben Lotan, Ph.D., at The University of Texas M. D. Anderson Cancer Center, Houston, says that the work by Wang et al. provides a possible explanation for the enhancing effect of ß -carotene supplementation on the development of lung cancer in smokers. However, he notes that there are several findings in the ferret study that are not characteristic of the response of human lungs to either tobacco smoke or ß -carotene. For example, chronic smoking often leads to the development of squamous metaplasia in humans, but no such change was seen in the lungs of ferrets exposed to tobacco smoke only. Further, the end point of the ferret study was not cancer development. Therefore, extension of the ferret findings to development of human lung cancers in smokers supplemented with high-dose ß -carotene must be done with caution.
Contact: Gabriele Amersbach, Tufts University, (617) 636-0412; fax (617) 636-4075. Editorial, Michael Courtney (713) 792-0663; fax (713) 794-4418.
Note: This memo to reporters is from the Journal staff and is not an official release of the National Cancer Institute (NCI) or Oxford University Press (OUP) nor does it reflect NCI or OUP policy. In addition, unless otherwise stated, all articles and items published in the Journal reflect the individual views of the authors and not necessarily the official points of view held by NCI, any other component of the U.S. government, OUP, or the organizations with which the authors are affiliated. Neither NCI nor any other component of the U.S. government nor OUP assumes any responsibility for the completeness of the articles or other items or the accuracy of the conclusions reached therein.
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