Christopher B. Umbricht, M.D., Ph.D.¹ and Saraswati Sukumar, Ph.D.²

1Department of Surgery, and ²Oncology and Pathology, Research, Breast Cancer Program, Johns Hopkins Oncology Center, Baltimore, MD 21231.

Evidence is mounting that telomerase is necessary, albeit not sufficient, for the malignant phenotype in most cancers. It also appears that telomerase activation is sufficient, albeit not necessary, for immortality at the cellular level. With very few exceptions, telomerase activity can be detected in breast cancer cells, while it is absent or undetectable in the corresponding normal tissue. This makes telomerase activity a valuable marker in at least three critical clinical circumstances: breast cancer screening, management of precancerous lesions, and prognosticating invasive disease. First, the unusual sensitivity of the telomerase assay makes it an attractive addition to the current cytologic assessment of minimal tissue samples, which could potentially make breast cancer screening as effective as a PAP smear. Second, an increasing number of ductal carcinoma in-situ of the breast (DCIS) is being detected by current screening procedures. DCIS lesions appear to be heterogeneous with respect to telomerase activity, and telomerase activation appears to precede the development of invasive cancer. Therefore, telomerase activity could be a useful adjunct in stratifying the risk of developing invasive breast cancer in patients with DCIS. Finally, there are indications that quantitation of telomerase activity may provide prognostic information in patients with invasive breast cancer, and may assist in the detection of minimal residual disease in lymph nodes or in peripheral blood. Journal of Women’s Cancer, 2 (3), 115-120, 2000.

Richard J. Santen, M.D.¹ and Harold A. Harvey, M.D.²

Jorge R. Pasqualini, D. Sc., Ph.D.

Hormones and Cancer Research Unit

75014 Paris; France

In the last years there has been an extraordinary development in the synthesis of new progestins. These compounds are classified, in agreement with their structure, in various groups, which include progesterone, retroprogesterone, 17-a-hydroxy-progesterone, 19 norprogesterones, 17-a-hydroxyprogesterone derivatives, androstane and estrane derivatives. The action of progestins is function of many factors: their structure, affinity to the progesterone receptor or to other steroid receptors, the target tissue considered, the biological response, the experimental conditions, dose, and metabolic transformation. In post-menopausal patients with breast cancer, positive responses have been obtained with medroxyprogesterone acetate and megestrol acetate, but the information using other progestins is very limited. However, extensive information on the effect of progestins has been obtained in in vitro studies using hormone-dependent and hormone-independent human mammary cancer cell lines. It has been demonstrated that in hormone-dependent breast cancer cells various progestins (nomegestrol acetate, medrogestone, promegestone) as well as tibolone (Org OD-14) and its metabolites are potent sulfatase inhibitory agents. Progestins can be also involved in the inhibition of mRNA of this enzyme. It has also been demonstrated that various progestins are very active in inhibiting the 17- a-hydroxysteroid dehydrogenase (17- a-HSD) for the conversion of estrone to estradiol (E₂). More recently, it was observed that the progestins promegestone, medrogestone or the compound tibolone and its metabolites stimulate sulfotransferase for the formation of estrogen sulfates. Consequently, the blockage in the formation of E₂ "via sulfatase", the inhibitory effect on 17- a-HSD for the formation of E₂ and the stimulatory effect on sulfotransferase activity by progestins can open interesting and new possibilities for therapeutic applications in breast cancer. JOURNAL OF WOMEN"S CANCER, 2(3), 135-143, 2000.

Jennifer I. MacGregor Schafer, Ph.D.¹ and V. Craig Jordan, Ph.D.²

Departments of Molecular Pharmacology¹ and Biological Chemistry², Robert H. Lurie Comprehensive Cancer Center, Northwestern University Medical School, Chicago, IL 60611

The evolution of antiestrogens over the last century has been a prototype for the development of drugs for novel applications. It is a classic example of the success of translational research from the laboratory to the clinic. From the discovery of compounds that could have had the potential as "morning after pills" to the estrogen receptor (ER) and selective ER modulators (SERMs), antiestrogens like tamoxifen have evolved from laboratory curiosities to the current standard of care in women with breast cancer. The success of tamoxifen has also encouraged the development of more widely used SERMs, like raloxifene and set the standard with which to compare all new drugs. Tamoxifen has been approved for the prevention of breast cancer in high risk pre and postmenopausal women and is currently being compared to raloxifene to prevent osteoporosis in the Study of Tamoxifen And Raloxifene (STAR) trial in 22,000 high risk postmenopausal women. However, the discovery that SERMs can have estrogen-like effects in bone and lower circulating cholesterol but at the same time prevent breast and, potentially, endometrial cancer has, for the first time, created a new dimension in drug development- the multifunctional preventive. SERMs hold the promise of a menu of medicines that can if appropriately applied, prevent osteoporosis, coronary artery disease, breast and endometrial cancer. JOURNAL OF WOMEN"S CANCER, 2 (3), 145-152, 2000

Hirohiko Matsumoto, Ph.D.¹ and Tetsuro Yamane, Ph.D.²

1Department of Biochemistry, Kyoto Prefectural University of Medicine Division of Surgery; ²Matsushita Memorial Hospital, Kyoto 602-8566, Japan

A large number of laboratory and animal studies over the last ten years have provided strong evidence of the anti-initiatiation and anti-promotor effects of green tea constituents, mostly due to their anti-oxidative activities. While epidemiological studies have been less conclusive, a number of recent cohort studies have also indicated convincingly that green tea has protective effects against a range of cancers, particularly those of the digestive tract. Further research is needed to establish more clearly the strength and range of effect and the exact pathways of metabolism and absorption, which remain unclear. Meanwhile, clinical studies are underway and should provide further information soon. As a non-toxic substance available in large quantity at low cost, green tea is an extremely promising chemopreventive agent. JOURNAL OF WOMEN"S CANCER, 2 (3), 152-158, 2000.

Ernst L. Wynder, a pioneer in disease prevention, passed away on July 14, 1999 after a valiant struggle against the very disease that he devoted his life's work to preventing. Many obituaries have already been written in honor of Ernst Wynder's outstanding contributions to science and health, and some repetition of fact and achievement is inevitable here. However, the photograph chosen above has not been published before. It depicts the excellent likeness of Dr. Wynder that was painted by John Boyd Martin in 1992, just as we at the American Health Foundation best remember him. This portrait is displayed at the Valhalla site of the American Health Foundation as a commemoration of the illustrious career of its founder.

Born in Herford, Germany on April 30, 1922, Ernst Wynder escaped from the Nazi regime through the efforts of his parents in 1938, emigrating via London to the United States, where he became a citizen in 1943. He served in the U.S. Army Intelligence Corps from 1943 to 1945, returning to Germany for a tour of duty near the end of World War II. Following his discharge he pursued a medical degree at Washington University School of Medicine, St. Louis, Missouri, graduating in 1950.

It was during the latter years of his degree course that Ernst Wynder, on his owns initiative and while still a medical student, gathered and collated information underscoring the strong association between cigarette smoking and lung cancer. The outcome of this study was the seminal publication in JAMA in 1950, co-authored by Wynder and his mentor Evarts Graham, which was later to become acknowledged as a landmark research paper on two occasions, in 1985 and 1992.

It was his conviction that the majority of cancers and some other chronic diseases were due to man's life-style or to environmental factors, thus implying that they were preventable. This conviction was ultimately the stimulus for him to seek funding from the National Cancer Institute, the American Cancer Society and private benefactors to establish a chronic disease prevention center, the American Health Foundation. Founded in 1969, the American Health Foundation under his leadership as President built a reputation as the only National Cancer Institute-designated laboratory cancer center dedicated to cancer prevention, a status it still holds today.

Ernst Wynder viewed himself as a global epidemiologist in which the world was his laboratory. But his contributions to science and health were not restricted to the realm of epidemiology. In 1976, he launched the international journal Preventive Medicine, devoted to publishing articles pertaining to disease prevention and public health. He remained as Editor-in-Chief of this Journal until the very end. His theme for the journal, and indeed for the work of the American Health Foundation, was the aphorism iterated consistently in his many lectures: "the function of medicine is to help people die young - as late in life as possible."

Dr. Wynder's strategy for disease prevention encompassed the incentive of promoting healthy living into the school education system. He fervently believed that the concept of a healthy life style could be ingrained into schoolchildren during their formative years. As a result, he conceived and initiated the Know Your Body (KYB) program at the American Health Foundation. First publicized in 1977, the KYB program persists today, promoting the teaching of healthy habits to all grades of schoolchildren through special curricula written by Wynder's colleagues and taught by dedicated teachers. His conviction that children should be the target of health promotion strategies was further manifested in his successful efforts in re-introducing the annual celebration of a National Child Health Day, first envisaged and proclaimed by U.S. President Calvin Coolidge in 1928.

Through the years, Ernst Wynder has strongly believed that nutrition plays a major role in cancer risk and prevention. He interacted with the food industry to encourage the concept of manufacturing health-promoting food products, and to this end, set up the Food and Nutrition Council at the American Health Foundation consisting of representatives from government, industry and academia. He was also a co-organizer of the first international meeting devoted to nutrition in cancer causation and prevention, sponsored by the National Cancer Institute and held in Key Biscayne in 1975.

Much of Ernst Wynder's work interests and activities have been focused on the health problems of women, and appropriately he was a member of the inaugural Editorial Board of Journal of Women's Cancer. His epidemiological research explored cancers of the breast, ovary, endometrium and cervix, and their relationship to environmental factors across demographic boundaries. The study on cervical cancer was awarded landmark status by the World Health Organization. Early in his career and along with Swedish collaborators, Dr. Wynder, identified iron deficiency as a key factor in the causation of Plummer-Vinson (aka Paterson-Kelly) syndrome of women, an oropharyngeal leukoplakia with a recognized complication of carcinoma of the oropharynx and upper esophagus. Subsequently, the supplementation of flour with iron resulted in eradication of this disease in Sweden. More recently Dr. Wynder developed one of the first nutrition intervention clinical trials, exploring the feasibility of low-fat dietary intervention after surgery in postmenopausal women with Stage I and II breast cancer for preventing recurrence. The WINS trial, as it is known at the American Health Foundation, is ongoing, with more than 30 clinical centers participating nationally.

Ernst Wynder stood tall amongst his peers and he received many awards and honors for his contributions to biomedical science. His pioneering incentive, his inspiration, and his far reaching vision have left us with a legacy that will carry through into the future, translating into healthier life-styles of generations to come.

Journal of Women’s Cancer, 2 (3), 159, 2000.