Project 1

Septin-2 in ovarian cancer

Collaborator: The Ribeiro Lab, Brown University, Women & Infants Hospital

Epithelial ovarian cancer is associated with poor survival rates due to the fact that patients are often diagnosed at late stages and become resistant to chemotherapy treatments. Novel targets for new therapies are needed. Recently, septin-2, a member of the septin family of GTP binding proteins, has been characterized in epithelial ovarian cancer and may act as a potential target for treatment. Septin-2 has been shown to be overexpressed in ovarian cancer human tissue and knockdown of septin-2 in cell lines results in a decrease in proliferation rates. We are further investigating the role of septin-2 in clear cell epithelial ovarian cancer.

Project 2

Human epididymis protein 4 (HE4) in ovarian cancer

Collaborator: The Ribeiro Lab, Brown University, Women & Infants Hospital

Human epididymis protein 4 (HE4) is a protein that is overexpressed in many ovarian cancers. It has diagnostic and prognostic abilities for epithelial ovarian cancer. An increase in HE4 serum levels in ovarian cancer patients is associated with disease progression. The specific biological function of HE4 is still largely unknown; however, studies investigating the functional effects of HE4 in ovarian cancer identified a role for HE4 in invasion and migration in ovarian cancer cell lines. We have demonstrated that exposure of ovarian cancer cells to recombinant HE4 promotes events associated with metastasis. We also investigated the signaling pathways mediated by HE4 and found that overexpression of HE4, or treatment of cells with recombinant HE4, led to upregulation of several transcripts coding for proteins related to events associated with metastasis. These results identified a direct role for HE4 in mediating malignant properties of ovarian cancer cells. Currently, we are advancing understanding of the role of HE4 in the progression of ovarian cancer through the implementation of an in vivo model. We are using the zebrafish embryo model to study human-relevant effects of HE4 on multiple aspects of ovarian tumor progression.

Project 3

Metalloestrogens and breast cancer

Collaborator: The Benoit Lab, Wheaton College

Breast cancer is one of the most common cancer diagnoses in women. Estrogens, a family of steroid hormones, are a major factor in promoting the growth and proliferation of breast tumors. The high incidence of breast cancer is also likely due, at least in part, to the presence of environmental estrogens. Recent data suggest that environmental estrogens— metalloestrogens—mimic the effect of estrogens and activate the estrogen receptor (ER). Copper, cobalt, nickel, lead, tin, chromium, and mercury have been shown to bind to the hormone-binding domain of the ER, and in some cases, block the binding of estrogen. While the effects of the metalloestrogen cadmium on breast cancer have been extensively studied, investigations into mercury’s effects on breast cancer are limited. Mercury is a toxicant of concern because it is known to bioaccumulate and biomagnify through the aquatic food chain, reaching harmful levels in top predators. Tuna and swordfish are two fish commonly associated with elevated mercury levels and consumed by humans. The consequences of prolonged mercury exposure on cancer development is unknown, and thus research into its effects on tumor progression is warranted. Using mercury analysis to determine intracellular mercury concentrations, we created a standardized protocol that maximizes cellular exposure to mercury. We demonstrated that treatment of human ER-positive breast cancer cells in culture with 1 nM of mercury promotes proliferation, whereas treatment with a thousand-fold higher concentration of 1 µM induces apoptosis. We are further investigating the effects of mercury on the progression of breast cancer in zebrafish embryos.