The role of human pygopus 2 in the proliferation of breast cancer cells

Abstract

Pygopus is a recently discovered downstream component of the Wnt signaling pathway required for β-catenin/Tcf dependent transcription. It has been proposed to act as a downstream mediator of transcription through its indirect interaction with β-catenin. Misactivation of Wnt signaling resulting in the overexpression of mitogenic Wnt target genes has been implicated in the progression of human cancer. In fact, aberrant Wnt signaling has been hypothesized to contribute to the formation of breast tumours. However, there are limited studies that conclusively address this question. Therefore, the purpose of this study was to examine the expression and requirement of the newly discovered Wnt signaling component Human Pygopus 2 (hPygo2) in this malignancy. -- To assess the expression of hPygo2 in malignant breast cancer cell lines and tumours, I characterized antiserum which specifically recognized hPygo2 protein. hPygo2 was found overexpressed in the nuclei of breast tumour cells and tissue but not in normal breast cells and tissue. Knockdown studies using siRNA or antisense oligonucleotides has demonstrated that bPygo2, but not β-catenin, was required for the growth of MCF-7 and MDA-MB-468 breast cancer cell lines and expression of the Wnt target gene Cyclin D1. Furthermore, I found that Pygopus I but not Pygopus 2 was required for mediating the Wnt signal through the key mediator, β-catenin. These novel observations suggest that the requirement for nuclear overexpression of hPygo2 can be independent of Wnt/β-catenin in the growth of breast carcinoma cells. Therefore, hPygo2 may be a more suitable therapeutic target than elements of the canonical Wnt pathway for the treatment of breast cancer.