Regulatory factors controlling stem cell identity and self-renewal are often 
active in aggressive cancers and are thought to promote their growth and 
progression. TCF3 (also known as TCF7L1) is a member of the TCF/LEF 
transcription factor family that is central in regulating epidermal and 
embryonic stem cell identity. We found that TCF3 is highly expressed in poorly 
differentiated human breast cancers, preferentially of the basal-like subtype. 
This suggested that TCF3 is involved in the regulation of breast cancer cell 
differentiation state and tumorigenicity. Silencing of TCF3 dramatically 
decreased the ability of breast cancer cells to initiate tumor formation, and 
led to decreased tumor growth rates. In culture, TCF3 promotes the sphere 
formation capacity of breast cancer cells and their self-renewal. We found that 
in contrast to ES cells, where it represses Wnt-pathway target genes, TCF3 
promotes the expression of a subset of Wnt-responsive genes in breast cancer 
cells while repressing another distinct target subset. In the normal mouse 
mammary gland, Tcf3 is highly expressed in terminal end buds, structures that 
lead duct development. Primary mammary cells are dependent on Tcf3 for 
mammosphere formation, and its overexpression in the developing gland disrupts 
ductal growth. Our results identify TCF3 as a central regulator of tumor growth 
and initiation, and a novel link between stem cells and cancer.