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Nischarin, a Novel Protein: a Strong Potential Tumor Suppressor and a Prognostic Marker of Breast Cancer
Tumor Cell Biology V
Background: Prior work in our lab has identified a novel protein termed Nischarin that blocks tumor cell migration/invasion, and which is absent or greatly reduced in highly invasive breast tumor tissues and cells. Nischarin is expressed only in estrogen receptor-positive human breast cancer cells such as MCF7, but not in MDA-MB 435 or MDA-MB 231. Furthermore, Nischarin inhibits cyclin D1 activity, which may explicate its effect on tumor invasiveness. Based on these observations, we suspect that Nischarin functions as a tumor suppressor of breast cancer. Objective/Hypothesis: The objective of this study is to determine whether Nischarin is a prognostic factor for breast cancer progression. Our hypothesis is that loss of Nischarin expression promotes tumorigenesis and that reintroducing Nischarin into breast cells lacking the protein induces growth suppression by blocking through the G1 check point. Specific Aims: (1) To study the relative protein expression of Nischarin in breast tumors, (2) to determine whether Nischarin inhibits breast tumor cell growth, and (3) to identify the signaling mechanism(s) by which Nischarin regulates tumor growth. Study Design : First , we will elucidate molecular profiling of Nischarin expression by studying the biological variance of breast tumors. Nischarin expression will be examined in a cohort of breast tumors from 300 patients that are arranged on tissue microarrays (TMAs) by immunohistochemistry. These data will be analyzed by comparing the number of tumors that down-regulate Nischarin and tumor type and prognosis. Second , we will examine if Nischarin inhibits anchorage-independent growth, an in vitro surrogate approach for in vivo tumor growth. Finally, we will examine whether Nischarin promotes growth inhibition by affecting cell cycle kinetics through Retinoblastoma (Rb) tumor suppressor pathway or through suppression of cell survival pathways. Potential Outcomes and Benefits of Research : The proposed studies will elucidate the significance of Nischarin in breast tumorigenesis and validate loss of Nischarin as a prognostic marker for metastatic breast cancers. Identification of targets of Nischarin in the signaling cascade(s) will help develop pharmacological approaches to activate the protein or to counteract the absence of Nischarin in highly metastatic tumors. Thus this study has a great promise for development of novel therapeutic strategies for highly advanced breast cancers.
One of the malignant characteristics acquired by tumor cells is the ability to invade into other tissues -- an activity that leads the way toward highly lethal metastatic disease. The genes that negatively regulate tumor growth are known as tumor suppressors; these genes normally block the function of genes that promote growth. We have identified a novel protein, Nischarin, which may function as a breast cancer tumor suppressor. We have shown that Nischarin inhibits cell invasion of breast cancer cells. Furthermore, our recent preliminary data show that Nischarin expression is down-regulated in highly invasive/metastatic breast tumors, while it is expressed normally in non-invasive tumors. The objective of the current study is to investigate the role of Nischarin in breast cancer progression. In this study we will measure the relationship between Nischarin expression and malignancy by examining an array of 300 small biopsies from human breast cancer patients. These small tumor biopsies are arranged as an array on a glass slide, and the expression of Nischarin will be examined by immunological approaches. These data will be independently scored by a panel of pathologists to avoid any bias. Specifically, we will use statistical approaches to correlate the expression pattern of Nischarin with known biological, clinical, and prognostic markers such as estrogen receptor status, tumor size, tumor grade, tumor type, and lymph node status. Importantly, we will look for indications that Nischarin may serve as a prognostic marker. In addition, the statistical analysis will reveal if there is any correlation of Nischarin expression with patient outcome/survival. The second part of the proposal will examine whether Nischarin inhibits tumor cell growth using different laboratory approaches to demonstrate the function of Nischarin as a tumor suppressor. Finally, we will determine how Nischarin inhibits breast cancer cell growth by deducing the mechanism of inhibition of Nischarin. Knowledge gleaned from this study may be helpful in designing drugs that can activate Nischarin or Nischarin-driven signaling cascades in Nischarin-deficient breast carcinomas to inhibit breast tumorigenesis. In summary, this study will help to assess whether Nischarin can be a good prognostic marker for breast cancer progression and will possibly identify Nischarin-mediated tumor-inhibitory pathways that may become novel targets for breast cancer therapies.