Six1 expands the mouse mammary epithelial stem/progenitor cell pool and induces mammary tumors that undergo epithelial-mesenchymal transition
Erica L. McCoy, … , Alana L. Welm, Heide L. Ford
Erica L. McCoy, … , Alana L. Welm, Heide L. Ford
Published August 24, 2009
Citation Information: J Clin Invest. 2009;119(9):2663-2677. https://doi.org/10.1172/JCI37691.
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Six1 expands the mouse mammary epithelial stem/progenitor cell pool and induces mammary tumors that undergo epithelial-mesenchymal transition

Abstract

Six1 is a developmentally regulated homeoprotein with limited expression in most normal adult tissues and frequent misexpression in a variety of malignancies. Here we demonstrate, using a bitransgenic mouse model, that misexpression of human Six1 in adult mouse mammary gland epithelium induces tumors of multiple histological subtypes in a dose-dependent manner. The neoplastic lesions induced by Six1 had an in situ origin, showed diverse differentiation, and exhibited progression to aggressive malignant neoplasms, as is often observed in human carcinoma of the breast. Strikingly, the vast majority of Six1-induced tumors underwent an epithelial-mesenchymal transition (EMT) and expressed multiple targets of activated Wnt signaling, including cyclin D1. Interestingly, Six1 and cyclin D1 coexpression was found to frequently occur in human breast cancers and was strongly predictive of poor prognosis. We further show that Six1 promoted a stem/progenitor cell phenotype in the mouse mammary gland and in Six1-driven mammary tumors. Our data thus provide genetic evidence for a potent oncogenic role for Six1 in mammary epithelial neoplasia, including promotion of EMT and stem cell–like features.

Authors

Erica L. McCoy, Ritsuko Iwanaga, Paul Jedlicka, Nee-Shamo Abbey, Lewis A. Chodosh, Karen A. Heichman, Alana L. Welm, Heide L. Ford

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Figure 9

Six1 overexpression significantly correlates with poor clinical outcome in breast cancers, and this significance is increased by coexpression of Ccnd1.

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Six1 overexpression significantly correlates with poor clinical outcome...
(A) In a study of 295 women with early-stage invasive breast carcinoma (45), high Six1 expression is associated with shortened time to metastasis, shortened time to relapse, and shortened breast cancer–specific survival (survival) (48). (B) In the same dataset, Ccnd1 overexpression alone does not correlate with shortened time to metastasis or relapse, or with shortened survival. (C) When Six1 and Ccnd1 are both overexpressed, their correlation to clinical parameters is exacerbated and the significance for poor prognosis is increased. (D) In a study of 240 patients diagnosed with invasive breast cancer of any stage (Pawitan and Ivshina) (46, 47), high Six1 expression is strongly associated with shortened time to relapse (48). Ccnd1 overexpression alone has no correlation with shortened time to relapse. When Six1 and Ccnd1 are both overexpressed, their correlation to shortened time to relapse is more significant. In both of these datasets, the mean value for Six1 and Ccnd1 expression in human breast cancers was used to divide the patients into high (above mean) and low (below mean) Six1– and Ccnd1–expressing animals.