Estrogen stimulates a newly discovered oncogene in the pituitary gland, setting the stage for cell proliferation, a team of Cedars-Sinai Medical Center researchers report in today's issue of the eminent scientific journal Nature Medicine.
"It has been known for many years that estrogen causes the pituitary to become hypervascular -- during pregnancy, it doubles in size -- but there has never been a proven link between estrogen and the mechanism of pituitary tumor development," said senior author Shlomo Melmed, M.D., director of Cedars-Sinai's Burns and Allen Research Institute and the Medical Center's senior vice president, Academic Affairs.
Pituitary tumors account for the most common intracranial neoplasms. Rarely malignant, they nonetheless cause a variety of disorders by generating excess hormones pivotal to growth and reproduction, thyroid and adrenal function.
This finding builds on the landmark 1997 discovery in Dr. Melmed's laboratory of the oncogene PTTG1 (pituitary tumor-transforming gene). Dr. Lin Pei, now a research endocrinologist at Cedars-Sinai, was primary author on a paper that described how overexpression of the gene leads to unbalanced division of chromosomes and subsequent tumor development (Mol. Endocrinol. 11,433-441; 1997).
Once the gene was sequenced in rat genomes, the Cedars-Sinai team sequenced and described its expression in human cells. A novel family of related PTTG oncogenes has since been identified at the institution.
Anthony P. Heaney, M.D., is the primary author of today's report, which has important implications for understanding human development, reproduction, adrenal and thyroid function, and pituitary cancer.
Pituitary tumors are more common in women than in men, reflecting estrogen's importance in tumor development. In men, pituitary tumors express excess estrogen receptors.
Awaiting publication is an important related discovery that PTTG is expressed in other forms of cancer, and that estrogen is linked to its insidious trigger of malignant cell growth in those organs as well.
Now researchers can begin to correlate expression of the gene with stages and lethality of various cancers, not just pituitary tumors, Dr. Melmed said.
A deeper understanding of various forms of PTTG and their actions will lead to improved cancer diagnosis, assessment of cancer progression, and treatment, particularly if ways can be found to disable these estrogen-driven accelerators of cell growth and transformation.
The paper's other authors, along with Heaney and Melmed, are Gregory A. Horwitz, Zhiyong Wang, Ph.D., and Regina Singson. The work was supported by a grant from the National Institutes of Health and a Fulbright Research Scholarship to Dr. Heaney. It was performed in the Doris Factor Molecular Endocrinology Laboratory at Cedars-Sinai.
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