Six1 expands the mouse mammary epithelial stem/progenitor cell pool and induces mammary tumors that undergo epithelial-mesenchymal transition
Erica L. McCoy, Ritsuko Iwanaga, Paul Jedlicka, Nee-Shamo Abbey, Lewis A. Chodosh, Karen A. Heichman, Alana L. Welm, Heide L. Ford
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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Research Article

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 2

Six1 overexpression leads to hyperplasia and precocious alveolar development.

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Six1 overexpression leads to hyperplasia and precocious alveolar develop...
(A) H&E-stained mammary gland sections show lipid droplets and alveolar expansion in low Six1– and high Six1–expressing animals, as compared with no Six1 controls (original magnification, ×20). Higher power insets show lipid droplets in mammary alveoli (arrows) in both low Six1 and high Six1 mammary glands (original magnification, ×63). (B) Mammary whole-mount analysis confirms diffuse hyperplasia in low Six1– and high Six1–expressing animals as compared with no Six1 animals (original magnification, ×1.25). (C) Quantification of epithelial versus fat and stromal content taken from scanned H&E-stained mammary gland sections from no Six1, low Six1, and high Six1 animals. Each point represents quantification of 1 mammary gland. The middle horizontal lines represent the mean, and error bars represent mean ± SEM.