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Biomarker Analysis In Ductal Carcinoma In Situ Of The Breast
Career Catalyst Research
With the increased use of screening mammography the incidence of ductal carcinoma in situ (DCIS) has increased and DCIS comprises 20-30% of all breast cancers diagnosed today. DCIS is considered an early stage in the progression to invasive cancer. The rationale for treating DCIS is to prevent progression to invasive disease. DCIS has been classified histologically by its growth pattern and nuclear grade. This method is poorly predictive of potential for recurrence after excision or progression to invasive disease. Unfortunately, molecular markers that play critical roles in progression of invasive breast cancer to metastatic disease, have not been promising as independent prognostic markers for local recurrence or progression of DCIS. Therefore, there is a critical need to identify novel predictors of DCIS progression. My goal is to identify novel biomarkers that will allow for more accurate prediction of clinical outcome for patients with DCIS. An overall and central hypothesis that I would like to test with this proposal, is that molecular alterations in DCIS, both in the epithelial component and the adjacent stromal fibroblasts, will be helpful in predicting invasive progression of DCIS. In the epithelial cells of DCIS I will analyze the prognostic value of transcription factors Stat5a/b and the Stat5 regulator, Caveolin-1, based on our experience with these markers as prognostic factors in human invasive breast cancer. In DCIS-associated fibroblasts, I will explore transcript profiling and in situ protein detection to identify changes associated with clinical outcome, especially focusing on the stromal-derived growth factor-1 (SDF-1), and its receptor, CXCR4. I collaboration with my mentors I am well positioned to carry out the proposed studies because of our extensive experience with signal transduction by Stat5 transcription factors and Caveolin-1, as well as CXCR4. Taking advantage of a large and unique clinical material of DCIS with outcome data, combined with novel technology for high density tissue arraying, these resources will position us well for systematic analysis of prognostic markers in DCIS.
Breast cancer is a serious health threat and the second commonest cause of death of cancer among women. Our understanding of this cancer is incomplete but we can identify certain precursor lesions of the breast such as ductal carcinoma in situ (DCIS) that commonly lead to invasive cancer. However, not all of these early lesions lead to invasive breast cancer. Currently, women with DCIS typically receive toxic therapies with potentially serious side effects although many of the patients may not need or benefit from such added therapy. This has near and long term effects such as damage to other tissues and even predisposition to other cancers such as leukemia. Since there has been a dramatic increase in mammographically detected DCIS identifying a subset of these lesions, which will progress to invasive carcinoma, becomes of great importance. In this study we will examine several promising molecular markers of DCIS that we hypothesize will help us predict which women will go on to develop breast cancer and, therefore, justify more intensive therapy.
The lesions of DCIS are composed of several different cell types. The most important cell is the precancerous epithelial cell but these cells are surrounded by a variety of other supportive cells. Abnormally growing cells still require a blood supply though expansion of blood vessels and a support architecture produced by other cells such as fibroblasts. These and other cells have been collectively referred to as the ?stroma? of a tumor. There has been a recent recognition that these stromal elements may be critical in supporting growth of invasive carcinomas. In our study we will investigate role of stroma in the development of cancer from precancerous lesions like DCIS. One of the key cells forming the stroma is the fibroblast. These cells are found throughout the body and contribute to supportive architecture in all of our tissues. In addition to the production of the protein collagen, a key building block of the surrounding cell architecture, fibroblasts secrete many other bioactive molecules.
Recently, it has been shown that the production of bioactive molecules called chemokines by fibroblasts may be permissive in formation metastasis. In this study we will specifically study the production of one chemokine, stromal derived factor-1 (SDF-1), and its receptor on DCIS cells, CXCR4. It is our hypothesis that the production of SDF-1 promotes not only metastasis but also evolution of DCIS to invasive carcinoma and the detection of SDF-1 may therefore identify appropriate patients with DCIS for more intensive therapy. Furthermore, blocking agents for SDF-1 may be useful for treatment of DCIS lesions to prevent progression in the future.