A Novel Prosenescence Therapy for Breast Cancer Treatment
Abstract
Senescence acts a crucial physiological barrier against breast cancer development. In normal breast epithelial cells, the activation of oncogenes or inactivation of tumor suppressor genes triggers the senescence barrier, which promotes an irreversible growth arrest and subsequent eradication of premalignant cells via the innate immune system. In order for breast cancers to fully develop, a premalignant breast cell must acquire the ability to overcome the senescence barrier and then maintain an anti-senescent state. However, very little is known regarding how these processes are controlled. Moreover, recent evidence has suggested that the senescence program could potentially be exploited therapeutically for breast cancer treatment. This research proposal will define a critically important anti-senescence pathway in breast cancer cells and determine whether it can be exploited as a "pro-senescence" therapy for breast cancer prevention and treatment. Therefore, this proposal directly addresses the following Breast Cancer Research Program Overarching Challenges: (1) identify what drives breast cancer growthdetermine how to stop it; (2) prevent breast cancer (primary prevention); and (3) revolutionize treatment regimens by replacing interventions that have life-threatening toxicities with ones that are safe and effective. In our preliminary studies, we sought to identify the critical regulators that maintain breast cancer cells in an anti-senescent state. Using an innovative cell imaging-based RNAi functional screening approach, we identified a largely uncharacterized enzyme called Fbxo44 as an important determinant in this process. Knockdown of Fbxo44 expression in a panel of breast cancer cell lines was found to induce profound and irreversible senescence, suggesting that breast cancers are "addicted" to Fbxo44 in order to maintain the anti-senescent state. Interestingly, Fbxo44 inhibition was also found to induce senescence in breast cancer cells independent of the major senescence regulatory proteins p53, pRb, and BRCA1, possibly uncovering a previously uncharacterized cellular senescence pathway. Our additional studies have revealed that Fbxo44 could play key roles in regulating DNA metabolism and chromatin structure -- processes intricately associated with cellular senescence. In this proposal, we will use molecular and biochemical approaches to elucidate the molecular mechanism(s) by which Fbxo44 maintains an anti-senescent state in breast cancer cells. This will include examining Fbxo44 s putative functional roles in regulating DNA metabolism and chromatin epigenetics. In addition, we will use a BRCA1 mouse model of breast cancer and human patient-derived xenografts to evaluate the therapeutic potential of Fbxo44 inhibition as both a pro-senescence therapy for breast cancer prevention and treatment. This research could ultimately lead to a novel therapeutic approach for breast cancer treatment via the induction of cellular senescence. Drugs that can inhibit Fbxo44 function would be expected to induce the irreversible senescence of breast cancer cells, thus halting their growth and metastasis progression and stimulating their eradication by the innate immune system. Since Fbxo44 functions independent of p53, pRb, and BRCA1, this pro-senescence therapy is predicted to be highly effective against a wide range of breast cancer subtypes, including those that have acquired resistance to conventional chemotherapy or targeted therapies. In addition, Fbxo44 inhibitor drugs could provide clinical benefit as a preventive treatment for individuals who carry BRCA1/2 mutations by inducing cellular senescence in premalignant lesions before they can progress to life-threatening breast cancers. The novel pro-senescence therapy ultimately developed from this research, which could be available for clinical testing within 3 years, will undoubtedly have a significant impact on lowering breast cancer mortality.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 29, 2016
- Source ID
- W81XWH1510383
Entities
People
- Charles Spruck
Organizations
- Sanford Burnham Prebys Medical Discovery Institute
- United States Army