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PLoS One. 2012;7(3):e33976. doi: 10.1371/journal.pone.0033976. Epub 2012 Mar 28.

Small molecule antagonists of the Wnt/β-catenin signaling pathway target breast tumor-initiating cells in a Her2/Neu mouse model of breast cancer.

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  • 1Department of Biochemistry and Biomedical Sciences, Centre for Functional Genomics, McMaster University, Hamilton, Ontario, Canada.

Abstract

BACKGROUND:

Recent evidence suggests that human breast cancer is sustained by a minor subpopulation of breast tumor-initiating cells (BTIC), which confer resistance to anticancer therapies and consequently must be eradicated to achieve durable breast cancer cure.

METHODS/FINDINGS:

To identify signaling pathways that might be targeted to eliminate BTIC, while sparing their normal stem and progenitor cell counterparts, we performed global gene expression profiling of BTIC- and mammary epithelial stem/progenitor cell- enriched cultures derived from mouse mammary tumors and mammary glands, respectively. Such analyses suggested a role for the Wnt/Beta-catenin signaling pathway in maintaining the viability and or sustaining the self-renewal of BTICs in vitro. To determine whether the Wnt/Beta-catenin pathway played a role in BTIC processes we employed a chemical genomics approach. We found that pharmacological inhibitors of Wnt/β-catenin signaling inhibited sphere- and colony-formation by primary breast tumor cells and primary mammary epithelial cells, as well as by tumorsphere- and mammosphere-derived cells. Serial assays of self-renewal in vitro revealed that the Wnt/Beta-catenin signaling inhibitor PKF118-310 irreversibly affected BTIC, whereas it functioned reversibly to suspend the self-renewal of mammary epithelial stem/progenitor cells. Incubation of primary tumor cells in vitro with PKF118-310 eliminated their capacity to subsequently seed tumor growth after transplant into syngeneic mice. Administration of PKF118-310 to tumor-bearing mice halted tumor growth in vivo. Moreover, viable tumor cells harvested from PKF118-310 treated mice were unable to seed the growth of secondary tumors after transplant.

CONCLUSIONS:

These studies demonstrate that inhibitors of Wnt/β-catenin signaling eradicated BTIC in vitro and in vivo and provide a compelling rationale for developing such antagonists for breast cancer therapy.

PMID:
22470504
[PubMed - indexed for MEDLINE]
PMCID:
PMC3314694
Free PMC Article

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