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Stem cells in normal breast development and breast cancer

Although it has been postulated that the epithelial components of the mammary gland arise through differentiation of a stem cell compartment, the isolation and characterization of these cells have been limited by the lack of defined cell surface markers and the development of suitable in vitro culture systems able to maintain these cells in an undifferentiated state. We have developed an in vitro culture system in which primary human mammary epithelial cells, isolated from reduction mammoplasties, are cultured as 'mammospheres' on non-adherent surfaces. We have demonstrated that mammospheres are highly enriched in undifferentiated cells capable of both self-renewal as well as differentiation into the three lineages of the mammary gland: myoepithelial cells, ductal epithelial cells, and alveolar epithelial cells. Affymetrix-based gene arrays demonstrate a significant overlap between genes expressed in mammospheres and those previously described in hematopoietic, neuronal, and embryonic stem cells. Utilizing these systems, we have found that both leukemia inhibitory factor as well as NOTCH play a role in cell fate determination. Whereas leukemia inhibitory factor affects primarily stem cell self-renewal, Notch signaling affects both self-renewal of stem cells as well as lineage-specific commitment of mammary progenitor cells. We hypothesize that mammary stem cells or their immediate progeny are targets for transformation during carcinogenesis. Normal stem cells and carcinoma cells share many characteristics, including self-renewal capacity, telomerase expression, ability to differentiate, resistance to apoptosis, and ability to home to specific sites. Important events in transformation may involve disregulation of pathways that control normal stem cell self-renewal, such as Notch, Wnt, LMO4, PTEN, and BMI1. In addition, the phenotypic heterogeneity found in human breast cancers best fits a stem cell model in which transformed stem or progenitor cells undergo aberrant differentiation. Using flow cytometry, we have identified a small population of cells within primary or metastatic human breast cancers that bear the cell surface phenotype CD44+CD24-/lowESA+Lineage- that have properties of tumor stem cells. As few as 200 of these cells are able to generate tumors in NOD-SCID mice, while the vast majority of cells in these tumors that lack this phenotype are incapable of tumor formation, even when tens of thousands of cells are injected. Consistent with a stem cell model, the tumorigenic stem cells generate tumors that recapitulate the phenotypic heterogeneity found in the original tumors. Current therapies have been developed by virtue of their ability to induce tumor regression and may selectively target more differentiated cells in tumors, while leaving the tumor stem cell population intact, accounting for treatment resistance and relapse. More effective therapies will require the targeting and elimination of the tumor stem cell population in breast cancer patients.

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Wicha, M., Dontu, G., Al-Hajj, M. et al. Stem cells in normal breast development and breast cancer. Breast Cancer Res 5 (Suppl 1), 50 (2003).

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