Research InterestsOvarian cancer, signaling pathways in ovarian cancer progression, steroid hormone signaling modulation by co-regulatory proteins
Reproductive Endocrinology & Infertility
Keywords: Cancer, Cell biology, Glucocorticoid receptors, Ovarian cancer; androgen receptor, steroid hormones, prostate cancer, endometrial receptivity, reproductive endocrinology
Detailed Description: Epithelial ovarian cancer (EOC) affects nearly a quarter million women worldwide each year and is the most lethal gynecological cancer in North America. Once thought to arise from a common cell of origin, studies now indicate the various histotypes of EOC may arise from non-ovarian cells, associate with distinct gene mutations, and diverge significantly in their clinical course. Of the various EOC histotypes, high-grade serous ovarian carcinoma (HGSOC) is the most prevalent and lethal. Compelling evidence provided by observational pathology studies and gene expression approaches support the paradigm-shifting concept that the cell of origin for HGSOC lies within the fallopian tube epithelium. Women with a germline mutation in BRCA1 or 2 are at the greatest risk of developing HGSOC. Additional identified risk factors for HGSOC are associated with an increased number of lifetime ovulatory events. We have found that gene expression profiles of non-malignant fallopian tube epithelial cells isolated from BRCA mutation carriers resemble that of HGSOC rather than non-malignant fallopian tube epithelial cells from control patients. This pattern is most pronounced in the luteal phase of the menstrual cycle and involves a proinflammatory signature. Ongoing studies are investigating the role of glucocorticoid receptors and downstream targets that may play a role in disease predisposition.
Studies from our laboratory have also shown that androgens alter the growth-inhibitory action of TGFβ in malignant and non-malignant ovarian epithelial cells. In recent work, we have identified a novel protein that may mediate these actions of androgen. Ongoing studies are investigating the role of this protein on TGFβ signaling and cross talk with other signaling pathways in the context of ovarian cancer.
Androgen-receptor associated protein 70 (ARA70) or NCoA4 was initially described as an androgen receptor specific co-activator. We have shown that NCoA4 is upregulated in EOC whereas a splice variant is expressed in invasive ductal breast carcinoma. We have also demonstrated that NCoA4 functions as a co-activator for the aryl hydrocarbon receptor, also known as the dioxin receptor. In recent work, we have found that NCoA4 interacts with tubulin and localizes to microtubules and particularly to the mitotic spindle. We are presently exploring the possibility that this novel protein plays a critical role in mitotic spindle formation, perhaps affecting cytokinesis.
Cell and tissue culture: Endothelial cells, primary fallopian tube epithelial cultures.
Procedures: Cell transfection assays, ChIP assays, gene expression analysis, immunohistochemistry, immunocytochemistry, invasion assays, qRT-PCR, RT-PCR, signal transduction characterization, western blot.
Analytical balances, benchtop centrifuge, blotting apparatus, confocal microscope, culture hood, culture incubators, cryostat, digital microscope, fluoresence microscope, fresh tissue sectioning systems, low- and high-speed centrifuge, low and ultralow freezers, plate reader, setups for electropherosis, stirrer/hot plate, vibratome, water baths.
Outside of the Department of Physiology:
Barry Rosen, OB/GYN
Maurice Ringuette, CSB
K. Joan Murphy, OB/GYN
Ellen Greenblatt, OB/GYN
Publications and Awards
Prolonged postovulatory proinflammatory signaling in the fallopian tube epithelium may be mediated through a BRCA1/DAB2 axis. Tone AA, Virtanen C, Shaw P, Brown TJ. Clin Cancer Res. 2012 Aug 15;18(16):4334-44. doi: 10.1158/1078-0432.CCR-12-0199. Epub 2012 Jul 2. PMID: 22753593