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Environmental Factor, April 2012

Hormones and Cancer highlights NIEHS/NTP paper

By Eddy Ball

Shannon Whirledge, Ph.D.

The Hormones and Cancer paper is Whirledge’s second publication as a member of the NIEHS Molecular Endocrinology Group and as first author. (Photo courtesy of Steve McCaw)

John Cidlowski, Ph.D.

Among his many honors for his research, Cidlowski has received the Edwin B. Astwood Award by the Endocrine Society. He has been with NIEHS since 1995. (Photo courtesy of Steve McCaw)

Darlene Dixon, D.V.M., Ph.D.

Dixon’s group studies rodent reproductive tissue and tissue samples taken from cycle-staged, premenopausal women that are part of the NIEHS/George Washington University Uterine Fibroid Study. (Photo courtesy of Steve McCaw)

The journal Hormones and Cancer is highlighting a new paper by NIEHS and NTP scientists as one of nine available free at the journal’s website (http://www.endo-society.org/journals/hormones_cancer.cfm)  . The bimonthly journal is beginning its third year, as a publication of the Endocrine Society, with an updated cover design and new leadership for its mission of advancing basic and clinical research on hormonally influenced cancers of endocrine glands.

In a message of congratulations to the paper’s first author, NIEHS postdoctoral fellow Shannon Whirledge, Ph.D., incoming Editor-in-Chief Carol Lange, Ph.D., wrote, “Hormones and Cancer has selected your recent paper for its high significance to our field and made it available as a free download.” As such, the paper forms part of the important first impression the journal makes on potential subscribers and prospective members of the Endocrine Society, who receive open access as part of their membership.

Whirledge, who is a member of the NIEHS Molecular Endocrinology Group headed by lead researcher John Cidlowski, Ph.D., co-authored the paper with Cidlowski, the senior author, and lead researcher Darlene Dixon, D.V.M., Ph.D., head of the NTP Molecular Pathogenesis Group, the second author.

Linking glucocorticoids to cellular proliferation in uterine fibroids

According to the study, it is reported that women over age 45 have more than a 60 percent lifetime risk of developing uterine fibroids, or leiomyomas, benign tumors of the uterus that are the leading cause for hysterectomies in the U.S. Fibroids pose a significant public health concern, due both to their prevalence and associated symptoms, including heavy bleeding, pain, infertility, and complications during pregnancy and labor.

Although estrogen has been clearly linked to fibroid development and growth, Whirledge and her colleagues suspected that other factors, including the steroid hormone glucocorticoid receptor (GR) binding, are involved. “We hypothesized that glucocorticoids might also block estrogen-regulated gene expression or biological functions important for leiomyoma growth,” they wrote, “[with] the potential to improve current strategies in the development of treatment for uterine leiomyomas.”

In vitro results suggest potential efficacy of in vivo intervention

Using immortalized human uterine leiomyoma cells and uterine smooth muscle cells supplied by Dixon, the team performed a series of detailed experiments to determine expression of GR and estrogen receptor, gene expression, and cell proliferation. The researchers were able to identify gene expression changes differentially regulated with treatment by both the synthetic glucocorticoid dexamethasone (Dex) and estrogen (E2) that may play a role in an antagonistic relationship. Dex and E2 had significant effects on the expression of genes involved in inflammatory and cell proliferation pathways. By interfering with cell phase progression, Dex treatment decreased cell proliferation, a key to stemming the aberrant growth characteristic of fibroids, and cotreatment with E2 did not reverse the effect.

“This study provides the first evidence that glucocorticoid and estrogen antagonism acts not only in a global manner, but also in a cell-specific manner in the uterus, specifically a uterine tumor in which many questions remain regarding the regulation of its endocrinology,” the researchers explained. “The clinical implications of the current findings are significant and have the potential to improve current strategies in the development of treatment for uterine leiomyomas.”

Looking ahead to clinical applications of their findings, the research team said that translating their discoveries into a therapeutic intervention will require further study to better understand the molecular processes involved in glucocorticoid antagonism and whether the findings can be replicated in an intact uterine environment.

Citations:

Lange CA. (http://www.springerlink.com/content/m358k18512h73j11/fulltext.pdf)  2012. Hormones and Cancer: A Bright Future. Horm Cancer. Apr;3(1-2):1-2.

Whirledge S, Dixon D, Cidlowski JA. (http://www.springerlink.com/content/b0g685w73x01674w/fulltext.pdf)  2012. Glucocorticoids Regulate Gene Expression and Repress Cellular Proliferation in Human Uterine Leiomyoma Cells. Horm Cancer; doi: 10.1007/s12672-012-0103-0 [Online 7 February 2012].




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