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RNA Interference as a Novel Approach to Target Cyclin E Overexpression in Breast Cancer
Background: Overexpression of cyclin E (Cyc E), an important cell cycle regulator, occurs in ~ 30% of breast cancer. The patients with high levels of cyc E at stage I died within five years of diagnosis and have a much shorter survival compared to those with low levels of cyc E. Thus, cyc E overexpression may be an important cause for breast cancer death and effective therapeutic approaches blocking its overexpression are urgently needed.
For years, there has been limited success to suppress oncogene overexpression by conventional methods such as antisense oligonucleotide because of its lacking of potency and specificity. However, the recent progress of small interference RNA (siRNA) technique allows to overcome those limitations, suggesting the potential of siRNA as a new type of drug for cancer treatment. Towards this goal, our laboratory showed promising results when we applied siRNA technique to target cyc E overexpression in breast cancer. Our studies demonstrated a depletion of cyc E overexpression, up to 90%, in breast cancer cells, indicating the potency of siRNA strategy for blockage of oncogene overexpression. Most notably, depletion of cyc E inhibited breast cancer cell proliferation and promoted tumor cell death, which occurred only in cyc E overexpressing cells.
Objective/Hypothesis: We hypothesize that cyc E siRNA may function as a novel and effective therapeutic agent to target cyc E-overexpressing breast cancer. We will test this by both breast tumor animal models and by combinational therapy.
Specific Aims/Study Design: (1) To determine the anti-tumor effects of cyc E siRNA using both subcutaneous and orthotopic breast tumor models in mice. An improved liposomal delivery system will be used for siRNA transfer by local or systemic treatment. We will compare the anti-tumor effects among different treatments to develop an optimal therapeutic strategy. (2) To examine the therapeutic efficacy of cyc E siRNA in combination with chemodrugs. We have demonstrated that combination of cyc E siRNA and doxorubicin exhibited a synergism on inhibition of breast cancer cell growth in cell culture. The synergistic effects from the combinations between cyc E siRNA and chemodrugs will be systematically evaluated in animals. We will also investigate the mechanisms mediating those synergistic effects.
Benefits: The success of this study not only will constitute a scientific basis for siRNA-based therapy for breast cancer and will also allow us to develop novel combinational therapies to enhance chemodrug efficacy and reduce breast cancer mortality.
Many breast cancers develop because different oncogenes (the molecule triggering cell proliferating) are overexpressed. One of the best known examples is the overexpression of Cyclin E; 30% of breast cancer patients overexpressed this oncogene. More frighteningly, the patients with high cyclin E expression have much lower survival rate and most of them died within five years of diagnosis (5). Thus, cyclin E overexpression may be an important cause for breast cancer mortality. Consequently, effective therapeutic approaches blocking cyclin E overexpression are urgently needed.
For decades, there has been limited success on development of effective tools to specifically suppress oncogene overexpression for breast cancer treatment. Fortunately, a novel technology called RNA interference or small interference RNA (siRNA) has recently been developed and has shown its promise as a new type of drug for cancer treatment due to its potency and specificity. To determine if this technology can effectively block cyclin E overexpression in breast cancer, we designed an siRNA specifically targeting on cyclin E and tested its effect in different breast cancer cells. We found that this siRNA could suppress cyclin E expression dramatically, up to 90% in cyclin E-overexpressed breast cancer cells, indicating the potency of this technique. We also found that depletion of Cyclin E in those cells induced significant inhibition of cell growth in cell culture. These promising results led us to believe that cyclin E siRNA may be a novel and effective therapeutic agent to treat breast cancer. Thus, in this proposal, we will focus on testing this promising agent by using several different scientific approaches. First, we will develop different breast tumor models in mice to examine the preclinical therapeutic effects of cyclin E siRNA. We will compare the anti-tumor effects of our cyclin E siRNA by different treatments to find an optimal therapeutic approach for breast cancer. The results from those mouse models will become the basis for us to develop our future clinic application on breast cancer patients. In addition, experiments will be carried out to assess if cyclin E siRNA, when combined with current chemodrugs, can increase thetherapeutic effects of the chemodrugs on breast cancer treatments.
The success of this study not only will constitute a scientific basis for cyclin E siRNA-based therapy for breast cancer and will also allow us to develop novel combinational therapies to enhance chemodrug efficacy and reduce breast cancer mortality.