A central issue of modern cancer biology is an understanding of molecular events that cause invasion of tumor cells into the surrounding stroma and vasculature, and promote their subsequent metastasis. Recent studies indicate that elevated tumor-endoglin expression is a positive indicator of prostate cancer patient survival. Conversely, low endoglin expression correlated with poor prognosis in prostate cancer patients with Gleason scores of 5-7.

Our published data demonstrate a requirement for endoglin's cytosolic domain in the inhibition of Cell migration, and suggest zyxin-related proteins as downstream effectors of endoglin-mediated Inhibition of cell migration. This proposal will use in vivo and in vitro approaches to examine the hypothesis that endoglin and zyxin-related proteins cooperate to regulate prostate cancer cell migration and metastasis. This research will deepen our understanding of metastasis in prostate cancer, and to better understand the relevance of endoglin to tumor neoangiogenesis, metastasis, prognosis and pharmacologic targeting potential.

The Notch receptors are a family of four related signaling molecules that are implicated in the regulation of breast cancer. This study will test the hypothesis that Notch4 intracellular domain contains conserved sequence motifs important for the promotion of tumor growth and angiogenesis, while Notch2 intracellular domain contains conserved sequence motifs that act to suppress tumor growth and angiogenesis. The confirmation of our hypothesis would aid in the complete description of signaling pathways that regulate mammary carcinoma cell growth, an important clinical issue since recent studies indicate that human breast cancer aggressive behavior correlates with Notch activity.

Twist is a basic-Helix-Loop-Helix transcription factor that plays both a positive and negative role in the regulation of early morphogenesis and differentiation of mesenchymal tissues. Small changes in Twist expression have profound phenotypic effects. Twist has recently been implicated in playing a role in metastasis of breast cancer cells. This study will test a model of Twist regulation as a means to control breast cancer progression. This is a step in the long-term goal to establish whether targeting Twist dimerization may be a fruitful therapeutic target to regulate metastatic growth. Future experiments will be directed to finding ways to modulate endogenous Twist dimer formation.

One of the poorest prognostic indicators for people with reproductive cancer is tumor progression from a hormone-dependant to a hormone-independent growth state. This research will investigate changes in the gene expression profile of ovarian granulosa tumor cells that have progressed to a hormone-independent growth state in vivo. It will also seek to validate the gene expression changes observed in hormone-independent GC tumors with quantitative real-time RT-PCR methodology.

There are three possible outcomes: 1) consistent evidence for differential expression of the genes of interest, 2) inconsistent evidence for differential expression of a given gene, 3) no evidence for differential expression of the genes of interest. Demonstration that the genes show significant, differential expression between hormone-dependant and hormone- independent GC tumor samples will provide sound evidence that these genes may be important to tumor progression.

The goal is to understand hereditary breast cancer in greater detail leading to a prospective clinical trial (one of the first of its kind in the country). Dr. Rasmussen will 1) expand clinical subtypes and refine genetic signatures for each subtype of previous gene expression profiles, 2) design a prospective clinical trial based on these profiles, and 3) include known familial and hereditary breast cancer cases in order to determine which clinical subtype they belong to. Gene expression profiling promises to provide much more powerful diagnostic, prognostic and therapeutically predictive tests and will influence patient care in the very near future.

Currently there are no models and few data concerning the effects of metals in human bronchial and bladder cells. The objective of this research is to focus on one metal of significant public health concern, arsenic, and begin to develop this model. The research will study arsenic caused chromosome damage and arsenic-induced chromosomal instability. Arsenic is considered a particularly important and dangerous environmental chemical because it is carcinogenic to humans and exposure is widespread.

Identification of granulosa cell tumor genetic determinants will lead to an understanding of the cellular mechanisms involved in tumorigenesis, with the ultimate goal of establishing early diagnostic and prevention measures that could be implemented to either prevent tumor development or metastatic advance. Hopefully, results of this investigation will lead to a research and career development grant to the National Institute of Health (NIH).

To fund the Support Service Fund so that underserved breast cancer patients throughout Maine may receive the services and supplies they need.

To fund cancer support groups and help launch a new prostate cancer initiative aimed at improving awareness and early detection as well as a Man-to-Man prostate cancer support group.

To help insure that a wide variety of cancer support programs continue to be offered at no charge to cancer patients and their families.

To provide scholarship to radiation therapy students attending a regional professional development conference.