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Prevention of chromosomal instability in breast cancer by indigo-derived CDK inhibitors
RISK and Prevention, Epidemiology
Aneuploidy is a hallmark of breast cancer and contributes importantly to malignant progression and therapy resistance. Aneuploidy is commonly caused by cell division errors that lead to chromosome missegregation. An important mechanism that subverts mitotic fidelity is the formation of multipolar mitotic spindles induced by abnormal numbers of centrosomes. Centrosome anomalies are very common in malignant breast tumors and develop early during malignant progression. Previous results from our laboratory have shown that centrosome overduplication requires cyclin-dependent kinase 2 (CDK2). Breast cancers frequently overexpress cyclin E or cyclin A, which function as activators of CDK2. Based on these results, this proposal aims to use a plant-derived CDK inhibitor, indirubin, to suppress centrosome-mediated cell division errors and aneuploidy in breast cancer cells. Indirubin and its derivatives show relatively little toxicity in pre-clinical models, which makes them suitable for tumor prevention or inhibition of tumor progression in chemo- or radiotherapy-free intervals. The Specific Aims are: (1) To determine the effects of indirubin and its synthetic derivatives on centrosome overduplication and aneuploidy in breast cancer cells and (2) To analyze the molecular mechanisms that underlie the anticipated effects of indirubin on aneuploidy. Our studies are designed to provide the proof-of principle that targeting chromosomal instability is feasible and will open new avenues for innovative approaches to prevent the deleterious consequences of increasing genome instability on the course of disease in women suffering from breast cancer.
Normal cells tightly control their number of chromosomes, the carriers of the genetic information. In breast cancer cells, this control is frequently disrupted and abnormal numbers of chromosomes arise, a condition termed aneuploidy. Aneuploidy is not only an important trigger of tumor progression by rendering cells more aggressive, it also impacts on the treatment response since it allows tumor cells to rapidly change their genetic composition and to become therapy resistant. This illustrates that inhibition of aneuploidy would potentially prevent malignant progression and increase the effectiveness of current or future therapies. Abnormal chromosome numbers commonly arise from errors during the cell division process (mitosis). In breast cancer, the formation of abnormal multipolar mitotic spindles is a particularly frequent event. Such abnormal spindles can pull chromosomes in different directions during cell division and cause numerical chromosomal changes in daughter cells. Mitotic spindles are organized by specialized cellular structures called centrosomes. Breast cancer cells frequently contain abnormally high numbers of centrosomes. It has recently become clear that dysregulation of enzymes that govern the cell division cycle including cyclin-dependent kinases (CDKs) are critical in mediating abnormal centrosome duplication and aneuploidy. This proposal therefore aims to exploit CDKs as targets to prevent centrosome-mediated cell division errors and aneuploidy. We will use a natural product derived from indigo-containing plants, indirubin, and its synthetic derivatives, which have been shown to potently block the enzymatic activity of CDKs. Indirubins have a low toxicity in pre-clinical models, which makes them ideal candidates for tumor prevention or to suppress tumor progression or relapse in chemo- or radiotherapy-free intervals. The specific aims are: (1) To determine the effects of indirubin-derived CDK inhibitors on abnormal centrosome numbers and aneuploidy in primary breast cancer cells, and (2) To analyze the molecular mechanisms that underlie the anticipated effects on aneuploidy. In summary, our goal is to suppress genomic instability by plant-derived natural products in order to constrain the catastrophic consequences of aneuploidy on the course of disease in women suffering from breast cancer.