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Cyclin D1 as a marker of DCIS recurrence
Tumor Cell Biology V
Background: Cyclin D1 overexpression is observed in 35-50% of breast cancers and is involved in cell cycle progression. Despite the expected effect of cyclin D1 overexpression on tumor growth, several studies indicated that cyclin D1 positive breast cancers relapse less frequently following lumpectomy and radiotherapy but how cyclin D1 provides such protective effect against breast cancer relapse has not been elucidated. We have obtained preliminary results that cyclin D1 down-regulates STAT3, a protein that is linked to tumor invasion and suppression of apoptosis. We found a negative correlation between cyclin D1 and STAT3 in primary breast cancers. In addition, low cyclin D1-high STAT3 cells are invasive in matrigel, while high cyclin D1-low STAT3 cells are apoptotic and non-invasive. However, another form of cyclin D1, cyclin D1b has been described but its effect on STAT3 remains unknown. In addition to its effect on invasion, cyclin D1 overexpression increases sensitivity of radiotherapy suggesting that drugs able to promote cyclin D1 accumulation may make radiotherapy more effective. We found that a novel drug named bortezomib is able to increase the levels of cyclin D1 raising the possibility that pre-treatment with bortezomib may increase sensitivity to radiotherapy. Objectives /Hypothesis: We hypothesize that the regulation of STAT3 by cyclin D1 is central to its beneficial effect on breast cancer. Further, we also hypothesize that bortezomib will make radiotherapy more effective in the specific context of cyclin D1 overexpression. Specific aim 1: Dissect the interaction between cyclin D1 and STAT3. Specific aim 2: Test the potential contribution of cyclin D1b on STAT3. Specific aim 3: Testing bortezomib pre-treatment as a radiotherapy sensitizer in the specific context of cyclin D1 overexpression. Study design: We will map the binding site of cyclin D1 to STAT3, create point mutations in the binding site and test their effects on STAT3 inhibition. In addition, we will design peptides derived from this binding site and test their ability to mimic cyclin D repression of STAT3. In aim 2, we will expand our analysis of the effect of cyclin D1/STAT3 by analyzing the ability of cyclin D1b to repress STAT3. In aim 3, we will test bortezomib treatment as a radiosensitizer in cyclin D1 overexpressing xenogrtafts. Potential Outcome and benefits of the Research: Provide a scientific rationale to support clinical studies aimed at validating the use of cyclin D1/STAT3 ratio as a way to predict the subset of patients that are at low versus high risk of local recurrence. Further, Bortezomib may be identified as a radiosensitizer.
Background: The management of ductal carcinoma in situ (DCIS) and early breast cancer remains a dilemma since it can recur after lumpectomy followed by radiation therapy and progress to invasive breast cancer. This observation suggests that some early lesions are resistant to radiation therapy and are capable of invading surrounding tissue. If this could be predicted, these patients may benefit from mastectomy at the onset rather than breast conservation management. This proposal focuses on the role of a protein called cyclin D1 as a way to predict the risk of breast cancer relapse. Cyclin D1 levels are abnormally high in 35-50% of breast cancers but these breast cancers do not relapse after conservative management. How cyclin D1 is protective against cancer relapse has not been studied. We found that cyclin D1 prevents cancer cells from invading tissue by blocking the action of STAT3. However, another form of cyclin D1, cyclin D1b, has been described but its ability to block STAT3 has not been studied. In addition, we found that a novel drug named bortezomib increases cyclin D1 levels. As high cyclin D1 levels are associated with a better response to radiotherapy, our observations suggest that bortezomib pre-treatment may make radiotherapy more effective. Specific aim 1: Dissect the interaction site between cyclin D1 and STAT3. Specific aim 2: Test the potential contribution of cyclin D1b on STAT3. Specific aim 3:Testing bortezomib as a radiotherapy sensitizer in cyclin D1 positive cells. Study design: We will use a number of molecular biology approaches to determine how cyclin D1 blocks STAT3. We will create a model to analyze cyclin D1 effect and use this model to test whether bortezomib can make radiotherapy more effective. Potential outcome and benefits of the Research: The hope is that our results will provide a scientific rationale to support clinical studies aimed at validating the use of cyclin D1/STAT3 ratio as a way to predict the subset of patients that are at low risk of local recurrence from those that are at high risk. Further, bortezomib may be identified as a drug able to make radiotherapy more effective.