A. Background: Breast cancer has now become a disease which, in most cases, is easily treatable if detected early or non-aggressive. However, the major cause of death for patients with breast cancer is metastasis of tumor cells from the primary tumor to secondary sites throughout the body. Determining the hallmarks to differentiate aggressive tumors versus non-aggressive tumors will not only in how clinicians choose to initially treat the patients, but also could potentially be used as therapeutic targets to specifically target metastatic tumor cells. Determining the factors involved in allowing circulating tumor cells to adhere to each other and to blood vessel walls could lead to improved treatment options for patients with metastatic breast cancer. However, paclitaxel has been shown to be ineffective for treatment of metastatic breast cancer. Proteins associated with the pericentriolar material (PCM) have been recently implicated as having major roles in microtubule nucleation and localization of some of these proteins has been shown to have changed in breast tumor cells versus normal cells. Thus the study of the proteins involved in the initial event of microtubule nucleation and the steps immediately following nucleation and how their interactions deviate from normal cellular activity could reveal crucial molecular biomarkers to treat metastatic breast cancer.
B. Rationale: We seek to study the process of microtubule nucleation in various breast tumor cell lines of diverse metastatic potential and understand the role of abnormal microtubule nucleation in breast cancer metastasis. Preliminary studies from our lab have shown a dissimilar staining pattern by immunofluorescence in the major microtubule nucleating prot...
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...llular proteins and the cell signaling pathways involved in microtubule nucleation to determine changes the metastatic potential of different cell lines. Cells will be transfected with fluorescently tagged proteins and observed by live cell microscopy. Invasion assays such as a wound healing assay can be used to measure changes in metastatic potential.
E. Relevance: Microtubules have long been targeted for treatment of primary tumors in breast cancer with paclitaxel and similar drugs that stabilize microtubules during mitosis and prevent cell division. However, these microtubule disrupting drugs have not been shown to be effective in the prevention of metastasis. By elucidating the mechanism by which aberrant microtubule nucleation occurs and the proteins involved, new molecular markers can be revealed to create new therapeutics for metastatic breast cancer.