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    Awarded Grants
    Stromal Caveolin-1 Regulation of Breast Cancer Growth and Metastasis.

    Scientific Abstract:
    Stromal caveolin-1 regulation of breast cancer growth and metastasis The aim is to determine the importance of Caveolin-1 (Cav-1) expression in the tumor microenvironment in the growth and metastasis of breast cancer. The hypothesis that we are testing is that Cav-1 expression in the stromal cells of a breast cancer suppresses the growth and invasive potential of the tumor. Background: Cav-1 is a major component of plasma membrane localised caveolae that are involved in multiple signalling pathways. Cav-1 is also found in the cytosol, where it is proposed to regulate cholesterol transport to the plasma membrane. Several lines of evidence implicate Cav-1 in tumorigenesis, including acting as a tumor suppressor in breast cancer. However, normal mouse and human breast epithelium does not express Cav-1; rather, it is expressed by the myoepithelial cells underlying the epithelium. Preliminary analysis of the expression of Cav-1 in whole sections of 32 breast cancers revealed that the median survival for patients whose stromal tissue remained Cav-1 positive was 12 years, compared to 3 years in cases where stromal Cav-1 expression was lost (p<0.02). We therefore hypothesize that stromal expression of Cav-1 exerts a paracrine influence on epithelial cell growth and that loss of Cav-1 is associated with unrestrained growth, increased invasiveness and metastasis in breast cancer. In support of this, the Cav-1 null mouse displays mammary ductal hyperplasia. Specific Aims: 1. To determine the consequences of Cav-1 expression in stromal tissues on disease-free survival and overall survival in patients with breast cancer. 2. To measure the consequences of loss of stromal Cav-1 expression on breast tumorigenesis, tumor growth and metastasis in mice null for Cav-1. 3. To explore the mechanism of stromal Cav-1 regulation of mammary epithelial cells in co-cultures of stromal and epithelial cells and in mammary transplant experiments. Study Design: We propose to analyse by IHC, a further 100 breast cancer sections to strengthen our preliminary findings on the importance of Cav-1 expression in stromal tissue on clinical outcome for patients. We will also measure breast tumor growth and metastasis in mice lacking Cav-1, compared to wild type mice. We will use two models: MMTV-Her2/neu mice crossed to the Cav-1 KO mice to measure growth and metastasis of spontaneous Her2/neu driven mammary tumors, and the growth of a metastatic mammary tumor line in Cav-1 null mice backcrossed onto a Balb/c background. Finally, we will look for the influence of Cav-1 in the paracrine regulation of epithelial cells by stromal cells using 3 dimensional cultures and by co-transplant of epithelium-free mammary tissue from either Cav-1 wt or null mice and mammary epithelial tissue from a Cav-1 wt mouse into cleared fat pads of recipient mice to observe ductal development in an environment of stroma with or without Cav-1. Potential Outcomes and Benefits of Research: The current focus of breast cancer research is the search for molecular signatures of progression from within the tumor cells. Whilst this approach is valid and provides a molecular signature that reflects the type of cancer, prognosis and potential targets for therapy, changes within the stromal compartment are often overlooked. It is becoming increasingly apparent that the microenvironment of a tumor is an active participant in tumor progression. This raises the potential for stromal therapy in treatment of breast cancer, once the relevant genetic targets are identified. Our preliminary clinical data using a training set of 32 breast cancers indicate that the expression levels of a stromal protein, Cav-1, profoundly alter the course of the disease. We propose that Cav-1 may be a target for stromal therapy, but much needs to be done before an understanding of its function at the tumor interface is understood.

    Lay Abstract:
    Stromal caveolin-1 regulation of breast cancer growth and metastasis Breast cancer is the most common cause of cancer death in western women. Whilst the primary tumor can often be eradicated successfully, in many cases, it may have already metastasized. In these cases, death is often caused by secondary tumors in the lungs, liver or bone. A critical need in the management of breast cancer patients is the ability to distinguish between patients at high risk of recurrence and spread to other organs (a process called metastasis) from those at low risk for these events. Presence of disease in the axillary lymph nodes is currently the best clinical measure of subsequent relapse and yet 30% of node-negative patients still experience a relapse. This highlights the need for additional prognostic markers that more accurately indicate patients at risk of relapse. Identification of genes linked to the metastatic process would assist in predicting prognosis and allow that subset of patients to be treated more aggressively or with adjuvant therapy as a first line treatment. For example, if genes that dictate spread to bone could be identified, patients with changes in the expression of these genes could be treated early with agents such as bisphosphonates to reduce the incidence of bone disease. In addition, identification of these genes is the first step towards designing specific therapies to target metastatic cells. Our long range goal is, therefore, to assist in the development of specific therapies or new diagnostic markers for metastatic breast disease. Using a mouse model of breast cancer spread to lungs and bone, we have identified a gene called caveolin-1 that is lost in cancers that spread more aggressively. Our preliminary data in human breast cancer indicates that when caveolin-1 expression is lost from the normal cells surrounding the tumor cells in the breast, the survival time for these patients is much reduced compared to those where caveolin-1 expression is retained. It is the aim of this project to investigate how this gene acts to suppress the spread of breast cancer using mouse models and co-cultures of normal cells and the cells that form breast tumours. We will also examine a larger number of breast tumors to strengthen our observation that expression of caveolin-1 in the normal cells around a tumor can predict patient outcome.