Hedgehog Signaling and Bmi-1 Regulate Self-renewal of Normal and Malignant Human Mammary Stem Cells

Abstract

The epithelial components of the mammary gland are thought to arise from stem cells with a capacity for self-renewal and multilineage differentiation. Furthermore, these cells and/or their immediate progeny may be targets for transformation. We have used both in vitro cultivation and a xenograft mouse model to examine the role of hedgehog signaling and Bmi-1 in regulating self-renewal of normal and malignant human mammary stem cells. We show that hedgehog signaling components PTCH1, Gli1, and Gli2 are highly expressed in normal human mammary stem/progenitor cells cultured as mammospheres and that these genes are down-regulated when cells are induced to differentiate. Activation of hedgehog signaling increases mammosphere-initiating cell number and mammosphere size, whereas inhibition of the pathway results in a reduction of these effects. These effects are mediated by the polycomb gene Bmi-1. Overexpression of Gli2 in mammosphere-initiating cells results in the production of ductal hyperplasia, and modulation of Bmi-1 expression in mammosphere-initiating cells alters mammary development in a humanized nonobese diabetic-severe combined immunodeficient mouse model. Furthermore, we show that the hedgehog signaling pathway is activated in human breast ''cancer stem cells'' characterized as CD44 + CD24 À/low Lin À . These studies support a cancer stem cell model in which the hedgehog pathway and Bmi-1 play important roles in regulating selfrenewal of normal and tumorigenic human mammary stem cells. (Cancer Res 2006; 66(12): 6063-71)

Beyond tumorigenesis: cancer stem cells in metastasis

“…For example, the Bmi-1 proto-oncogene plays an essential role in the regulation of self-renewal for both leukemia stem cells as well as HSCs [42,43]. Bmi-1 is also required for neural stem cell selfrenewal and is highly expressed in brain tumor CSCs [35,44,45]. In contrast, loss of the PTEN tumor suppressor functionally distinguishes leukemia stem cells from normal HSCs [46].…”

Relevance of circulating tumor cells, extracellular nucleic acids, and exosomes in breast cancer

“…Bmi-1 (PcG protein B lymphoma Mo-MLV insertion region 1 homolog), was initially identified as an oncogene cooperating with c-myc in the development of murine pre-B-cell lymphomas [121]. Bmi-1 plays an essential role in maintaining the self-renewal of normal and malignant human mammary stem cells [122]. Over-expression of Bmi-1 is reported and correlated to poor clinical prognosis in solid tumors of breast [123], lung [124] and colon [125] cancers; to name but a few.…”

Distinct methylation profile of mucinous ovarian carcinoma reveals susceptibility to proteasome inhibitors

“…Epigenetic silencing of tumor suppressor genes by promoter hypermethylation is commonly observed in human cancers 16, 17. DNA methylation may serve as a marker for the differential diagnosis of cancer and as a means of assessing the prognosis of cancer patients 18, 19, 20, 21.…”