The work comes out of the molecular therapeutic laboratory directed by Richard G. Moore, MD, of Women & Infants' Program in Women's Oncology. Entitled "HE4 expression is associated with hormonal elements and mediated by importin-dependent nuclear translocation," the research was recently published in the international science journal Scientific Reports, a Nature publishing group.
The goal of the study was to investigate the role of the hormone HE4 in modulating an ovarian cancer's response to hormones and hormonal therapies. HE4 is a biomarker that is elevated in ovarian cancer and is known to play a role in resistance to chemotherapy.
"There is little known about the biologic functions of HE4 but we did know that there were hormonal responsive elements within the promoter region of the HE4 gene, which regulates gene expression. For this reason, we hypothesized that steroid hormones could influence expression of HE4 in ovarian cancer," Moore explains.
The study resulted in multiple findings:
- Hormonal therapies like Tamoxifen and Fulvestrant are effective because they bind the estrogen receptor. If cells have less estrogen receptor expression, these drugs can't do their job. This, the researchers believe, is due to epigenetic modifications which modify the DNA structure but not the DNA sequence itself. Overexpression led to the epigenetic modification known as decreased DNA methylation in cell culture and in human tissue samples.
- Treatment of ovarian cancer cells with Tamoxifen and Fulvestrant all cause HE4 to translocate to the nucleaus, where it can then effect further gene expression in cancer cells.
- Using the drug Ivermectin, the researchers were able to inhibit the protein import in-4, which then inhibited HE4 from translocating to the nucleus. If HE4 can't enter the nucleus, it cannot affect gene expression. The ability to block HE4 from entering the nucleus restored sensitivity to hormonal therapy.
"We are not certain but believe this might mean there could be a subset of women whose tumors are more likely to respond to hormonal therapy. Moreover, we might be able to eventually identify which tumors these are and target treatment," Moore says.
His lab will continue to investigate the expression of estrogen receptors in both primary and recurrent ovarian cancers and how that relates to HE4 expression. In addition, he and other researchers will investigate how importin inhibitors may play a role in addressing chemoresistance to standard therapeutics, particularly in HE4 overexpressing tumors.
About Women & Infants Hospital
Women & Infants Hospital of Rhode Island, a Care New England hospital, is one of the nation's leading specialty hospitals for women and newborns. The primary teaching affiliate of The Warren Alpert Medical School of Brown University for obstetrics, gynecology and newborn pediatrics, as well as a number of specialized programs in women's medicine, Women & Infants is the eighth largest stand-alone obstetrical service in the country with nearly 8,400 deliveries per year. In 2009, Women & Infants opened the country's largest, single-family room neonatal intensive care unit.
New England's premier hospital for women and newborns, Women & Infants and Brown offer fellowship programs in gynecologic oncology, maternal-fetal medicine, urogynecology and reconstructive pelvic surgery, women's mental health, neonatal-perinatal medicine, pediatric and perinatal pathology, gynecologic pathology and cytopathology, and reproductive endocrinology and infertility. It is home to the nation's only mother-baby perinatal psychiatric partial hospital, as well as the nation's only fellowship program in obstetric medicine.
Women & Infants has been designated as a Breast Center of Excellence from the American College of Radiography; a Center for In Vitro Maturation Excellence by SAGE In Vitro Fertilization; a Center of Biomedical Research Excellence by the National Institutes of Health; and a Neonatal Resource Services Center of Excellence. It is one of the largest and most prestigious research facilities in high risk and normal obstetrics, gynecology and newborn pediatrics in the nation, and is a member of the National Cancer Institute's Gynecologic Oncology Group and the National Institutes of Health's Pelvic Floor Disorders Network.
Journal
Scientific Reports