title: Control of breast cancer growth and initiation by the stem cell-associated transcription factor TCF3.
abstract: 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.
authors.affiliation: Authors' Affiliations: Department of Developmental Biology and Cancer Research, Institute for Medical Research-Israel-Canada, Hadassah School of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Slyper
authors.forename: Amit
authors.initials: A
authors.lastname: Shahar
authors.forename: Anat
authors.initials: A
authors.lastname: Bar-Ziv
authors.forename: Roy Z
authors.initials: RZ
authors.lastname: Granit
authors.forename: Tamar
authors.initials: T
authors.lastname: Hamburger
authors.forename: Bella
authors.initials: B
authors.lastname: Maly
authors.forename: Tamar
authors.initials: T
authors.lastname: Peretz
authors.forename: Ittai
authors.initials: I
authors.lastname: Ben-Porath
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D020133:Reverse Transcriptase Polymerase Chain Reaction; D059467:Transcriptome
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; C407909:TCF3 protein, human