Cancer cells share certain traits with normal stem cells, and these are thought to promote tumor growth and progression. Basal-like tumors are a poorly differentiated, extremely aggressive subtype of breast cancer, and possess progenitor-like traits. We have found that the gene encoding the TEAD4 transcription factor is highly expressed in basal-like breast tumors. TEAD4 is a downstream effector of the Hippo pathway, which controls stem cell function, organ size and apoptosis, and promotes tumorigenesis. In Drosophila, the Vestigial protein is a master regulator of wing development, acting in complex with Scalloped, the ortholog of TEAD4. Interestingly, we found that VGLL1, the human ortholog of vestigial, which function's is poorly characterized, is also overexpressed in aggressive breast cancers, together with TEAD4Hence, we hypothesized that TEAD4 and VGLL1 may collaborate in tumorigensis and determination of differentiation state of basal-like breast cancer.
We found that human cell lines overexpressing TEAD4 or VGLL1 displayed highly increased breast cancer growth and metastasis when injected into the mammary glands of immunodeficient mice. Moreover, co-expression of the genes had a dramatic effect on growth rate and metastasis.
The finding that EGFR and VGLL1 are both highly expressed in our cell line model, led us to suspect a possible link between them. Indeed, upon EGFR inactivation we saw reduced levels of VGLL1. On the protein level, VGLL1 knockdown was observed to decrease phosphorylated-EGFR levels. Taken together, these results suggest VGLL1 modulates EGFR signaling and transcriptional regulation.
Our results indicate that the TEAD4 transcription factor, potentially in collaboration with VGLL1, promotes breast cancer growth. We intend to establish the physical and functional interaction between TEAD4 and VGLL1 and study the mechanisms by which they promote tumor growth independently and collaboratively, as well as their effect on EGFR signaling.
