Abstract
Drug resistance and cancer metastasis are two major problems in cancer research. During a course of therapeutic treatment in Brca1-associated tumors, we found that breast cancer stem cells (CSCs) exhibit an intrinsic ability to metastasize and acquire drug resistance through distinct signaling pathways. Microarray analysis indicated that the cytoskeletal remodeling pathway was differentially regulated in CSCs, and this was further evidenced by the inhibitory role of reagents that impair this pathway in the motility of cancer cells. We showed that cisplatin treatment, although initially inhibiting cancer growth, preventing metastasis through blocking cytoskeletal remodeling, and retarding CSC motility, eventually led to drug resistance associated with a marked increase in the number of CSCs. This event was at least partially attributed to the activation of PI3K signaling, and it could be significantly inhibited by co-treatment with rapamycin. These results provide strong evidence that cytoskeletal rearrangement and PI3K/AKT signaling play distinct roles in mediating CSC mobility and viability, respectively, and blocking both pathways synergistically may inhibit primary and metastatic cancer growth.
Highlights
Metastasis is a serious problem that claims the lives of breast cancer patients
We showed that cisplatin treatment, initially inhibiting cancer growth, preventing metastasis through blocking cytoskeletal remodeling, and retarding cancer stem cells (CSCs) motility, eventually led to drug resistance associated with a marked increase in the number of CSCs
Cisplatin Induces Drug Resistance That Is Associated with an Increase in the Cancer Stem Cell Subpopulation—To study the drug response of Brca1 mutant mammary tumors, we transplanted cells isolated from primary tumors of Brca1 mutant mice into nude mice and treated the recipient mice with several drugs that are commonly used for various forms of cancers, including ICI182,780, U1026, mifepristone (RU-486), rapamycin, and cisplatin (16 –19)
Summary
Results: Rapamycin and cisplatin synergistically inhibit CSC-mediated primary and metastatic cancer growth by blocking mTOR signaling and cytoskeletal remodeling. Conclusion: Cancer stem cells are involved in both primary and metastatic cancer growth of Brca tumors through distinct signaling pathways. Drug resistance and cancer metastasis are two major problems in cancer research. During a course of therapeutic treatment in Brca1-associated tumors, we found that breast cancer stem cells (CSCs) exhibit an intrinsic ability to metastasize and acquire drug resistance through distinct signaling pathways. This event was at least partially attributed to the activation of PI3K signaling, and it could be significantly inhibited by co-treatment with rapamycin These results provide strong evidence that cytoskeletal rearrangement and PI3K/AKT signaling play distinct roles in mediating CSC mobility and viability, respectively, and blocking both pathways synergistically may inhibit primary and metastatic cancer growth
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