Scientists from three NIEHS laboratories jointly hosted Richard Santen, M.D., on March 24 for a special lecture titled “Tissue Selective Estrogen Complexes (TSECs): Effects on Experimental Breast Cancer.” TSECs are being studied for their potential to reduce symptoms of menopause without promoting breast cancer.
Santen, from the University of Virginia, is a past president of the Endocrine Society and a long-time collaborator of Chris Jewell, a biologist in the NIEHS Signal Transduction Laboratory, which co-sponsored Santen’s visit, together with the Reproductive and Developmental Biology Laboratory and the Epigenetics and Stem Cell Biology Laboratory.
Slowing the growth of existing tumors
The Women’s Health Initiative, a program started by the National Institutes of Health in 1991, led to the discovery that combined estrogen-progesterone therapy for symptoms of menopause could increase risk of breast cancer. This piqued Santen’s interest. “We spent some time trying to develop a model to explain these findings,” he said.
In developing his model, Santen found that approximately seven percent of women have undiagnosed breast cancer. Because these tumors take an average of 200 days to double, first diagnosis of a one-centimeter tumor may occur as long as 20 years after the first cancer cells develop. Santen suggested that estrogen, along with a progestogen, a class of hormones that includes progesterone, shortened the doubling time to 150 days, causing existing cancer cells to grow more quickly and to be diagnosed sooner.
By contrast, tamoxifen and similar drugs increase the doubling time, slowing the rate at which cancers grow, leading to later diagnosis. Santen observed that a scientist relying only on epidemiological studies might falsely conclude that estrogen was causing cancer, and tamoxifen was preventing it. “This is tumor suppression, not tumor prevention,” he said.
Breast cancer and menopause
However, tamoxifen did not reduce symptoms of menopause, such as hot flashes. Looking for a better approach, Santen became interested in TSECs, which combine one or more estrogens with compounds that inhibit estrogen activity. The combination of an estrogen and anti-estrogen has unique properties, different from those of either compound alone.
Santen is particularly excited by a compound that combines conjugated equine estrogen and bazodoxifene (BZA). “With this combination, we are trying to treat all the symptoms of menopause, while at the same time preventing breast cancer,” he said.
Santen explained that BZA opposes the action of estrogen in breast tissue, but not in bone tissue, hypothetically resulting in increased bone density and decreased breast cancer in menopausal women. “If this really does prevent breast cancer and relieves menopausal symptoms, it could prevent a huge number of breast cancers, ultimately,” he said.
More multi-laboratory collaborations to come
Throughout the year, NIEHS laboratories sponsor seminars related to their specialties. Because of the cross-cutting nature of much environmental health research, institute scientists recognize the benefits of collaborating on information sharing and research.
“[Santen’s] research is on a topic that spans the breadth of all three laboratories, and we thought it would be a good idea when we had a speaker like that to bring us all together,” said John Cidlowski, Ph.D., chief of the Signal Transduction Laboratory. “Seeing how well it worked, we plan to do it again.”
(Simone Otto, Ph.D., is an Intramural Research Training Award fellow in the NIEHS Ion Channel Physiology Group.)