Department of Developmental Biology and Cancer Research, Institute for Medical Research-Israel-Canada, Hadassah School of Medicine, The Hebrew University of Jerusalem, Jerusalem
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 is a member of the TCF/LEF transcription factor family that is pivotal 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 the breast cancer cell differentiation state and tumorigenicity. Silencing of TCF3 in basal-like breast cancer cell lines disrupted cell proliferation and morphology, and TCF3-silenced cancer cells form smaller and less invasive tumors. Importantly, we found that TCF3 enhances cancer stem cell-associated traits, including mammosphere formation, the CD44high/CD24low marker profile, and, importantly, tumor initiating capacity upon implantation in mouse mammary glands. TCF3 is known to suppress Wnt target genes and self-renewal in ES cells; in contrast, we found that in breast cancer cells TCF3 binds and activates a subset of Wnt target genes while suppressing a distinct set of Wnt targets. Moreover, upon stimulation with Wnt3A, cells silenced for TCF3 showed reduced mammosphere formation ability compared to treated controls, suggesting that TCF3 can act also as a positive regulator of the Wnt signaling. Tcf3-silenced mouse mammary epithelial cells formed fewer mammospheres and showed reduced tissue reconstitution ability, while transgenic Tcf3 overexpression disrupted mammary ductal growth. Together, our results identify TCF3 as a key regulator of breast cancer growth and initiation, and a novel link between stem cells and cancer.
