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

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.

• Authors: Robin M Hallett, Maria K Kondratyev, Andrew O Giacomelli, Allison M L Nixon, Adele Girgis-Gabardo, Dora Ilieva, John A Hassell
• Journal: PloS one (PLoS One) Vol. 7 Issue 3 Pg. e33976 ( 2012) ISSN: 1932-6203 [Electronic] United States
• PMID: 22470504 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• PKF118-310
• Pyrimidinones
• Triazines
• Wnt Proteins
• beta Catenin
• Receptor, ErbB-2

Topics

• Animals
• Breast Neoplasms (drug therapy, metabolism, pathology)
• Cell Proliferation (drug effects)
• Cells, Cultured
• Disease Models, Animal
• Epithelial Cells (drug effects, metabolism)
• Female
• Gene Expression Profiling
• Mammary Glands, Animal (cytology)
• Mice
• Neoplastic Stem Cells (drug effects, metabolism)
• Pyrimidinones (pharmacology, therapeutic use)
• Receptor, ErbB-2 (metabolism)
• Triazines (pharmacology, therapeutic use)
• Wnt Proteins (antagonists & inhibitors, metabolism)
• Wnt Signaling Pathway (drug effects)
• beta Catenin (antagonists & inhibitors, metabolism)