These new findings could significantly advance the understanding of the effects of estrogen in breast cancer and point the way towards new and potentially more effective treatments of the disease.
The new study was published this week in an advanced online edition of the Proceedings of the National Academy of Sciences.
Estrogen has long been linked to the development of breast cancer, both through the stimulation of breast cell growth, which can lead to mutation, and through estrogen metabolism, which can interfere with apoptosis and DNA repair. Estrogen receptors mediate the majority of the actions of estrogen, including the metastatic growth of breast cancer cells, and are an important marker in therapy; readable levels of estrogen receptor proteins are expressed in a large portion of human breast cells.
Professor Thomas F. Deuel, M.D., a Scripps Research scientist who participated in the study said, "The estrogen and anti-estrogen signaling pathways mediated by this new receptor could explain why some breast cancers grow worse or become resistant to anti-estrogen therapy, specifically the drug tamoxifen, which blocks estrogen signaled responses through ER-a66 in breast tissue." According to the National Cancer Institute, anti-estrogen therapy is most often used in postmenopausal women whose tumors grow in response to the hormone.
"Worldwide, breast cancer is the most common form of cancer in women and the second most common cause of death for women in the United States," Deuel said. "The toll in suffering and mortality is especially devastating because breast cancer strikes women at a time in their lives when they are most productive and they are busy with children and raising a family. This continues despite great progress in the diagnosis and development of treatment strategies in human breast cancer. Our new study may help in finding a solution to remaining critical questions surrounding the mechanisms that drive breast cancer."
Earlier research into how hormones signal various functions in hormone-responsive tissues led to the identification of the human estrogen receptor (hER), which is mediated by specific nuclear receptors including hER-?66. However, questions regarding the functional significance of cell plasma membrane-initiated estrogen signaling in human breast cancer and in other estrogen responsive tissues remain largely unanswered.
The significance of a cell plasma membrane-based estrogen receptor that triggers estrogen signaling has been a point of controversy for a long time, the researchers said. The study showed that hER-?36, unlike other estrogen receptors, is predominantly localized on the cell plasma membrane that surrounds the cell cytoplasm; the receptor stimulates cell growth by estrogens and anti-estrogens through activation of the MAPK/ERK signaling pathway-a pathway that is involved in cell differentiation and growth. According to the study, this new finding could lead to the potentially "critically important conclusion" that estrogens and anti-estrogens can both stimulate cell proliferation through membrane-associated hER-?36.
"By identifying and cloning a novel form of the human estrogen receptor, our studies suggest that hER-?36 may have a greater potential to signal estrogen stimulated membrane responses than hER-a66," Deuel said. "The results of our experiments demonstrate that the presence of hER-?36 strikingly inhibits both estrogen-dependent and estrogen-independent transactivation functions-which result in protein production-mediated by ER-?66."
The researchers expressed surprise that anti-estrogen treatments such as tamoxifen stimulate cell growth and that the anti-estrogens appear to have a stronger and a more prolonged activation of the MAPK/ERK signaling pathway than the estrogens tested.
These findings, the study said, support the conclusion that tamoxifen functions as both agonist and antagonist of estrogen signaling and that the expression of hER-a36 may be involved in the development of tamoxifen-resistant human breast cancer. This raises the possibility that estrogen-activated ER-a36 signaling initiated in the cell plasma membrane may actually accelerate the course of tamoxifen-resistant human breast cancer.
"The apparent ability of hER-?36 to trigger membrane-initiated estrogen and anti-estrogen signaling that leads to cell growth makes it an important new member of the estrogen signaling pathway," Deuel said. "Its potential to antagonize estrogen-stimulated transactivational functions transduced by hERa66 is also an important feature of the new receptor's functional responses to estrogens. Based on our new findings, further studies of this potentially very important protein are likely to significantly advance our understanding of the diverse physiological and pathological effects of estrogen action."
Other authors of the study include ZhaoYi Wang, XinTian Zhang, Brian W. Loggie of Creighton University; Peng Shen (Zhejiang University PR China); and Yunchao Chang of Scripps Research.
This work was supported by the National Institutes of Health and the Nebraska Tobacco Settlement Biomedical Research program.
About The Scripps Research Institute
The Scripps Research Institute, headquartered in La Jolla, California, in 18 buildings on 40 acres overlooking the Pacific Ocean, is one of the world's largest independent, non-profit biomedical research organizations. It stands at the forefront of basic biomedical science that seeks to comprehend the most fundamental processes of life. Scripps Research is internationally recognized for its research into immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune, cardiovascular, and infectious diseases, and synthetic vaccine development. Established in its current configuration in 1961, it employs approximately 3,000 scientists, postdoctoral fellows, scientific and other technicians, doctoral degree graduate students, and administrative and technical support personnel.
Scripps Florida, a 364,000 square-foot, state-of-the-art biomedical research facility, will be built in Palm Beach County. The facility will focus on basic biomedical science, drug discovery, and technology development. Palm Beach County and the State of Florida have provided start-up economic packages for development, building, staffing, and equipping the campus. Scripps Florida now operates with approximately 160 scientists, technicians, and administrative staff at 40,000 square-foot lab facilities on the Florida Atlantic University campus in Jupiter.
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