TSC22 in mammary gland development and breast cancer

Abstract

Mammary gland involution is characterised by a high degree of apoptosis. By identifying genes that are upregulated at this developmental stage, we aimed to discover key factors that are involved in the induction of mammary epithelial cell death and therefore present potential tumour suppressors for breast cancer. Among 96 genes recently identified as specifically upregulated early during involution were the transforming growth factor beta (TGFβ)-stimulated clone 22 homologue (TSC-22/TGFβ1-induced transcript 4) and TGFβ3 [1]. TGFβ3 has recently been shown to be necessary for induction of apoptosis during mammary gland involution, while TSC-22 overexpression can lead to cell death. We have therefore tested whether TSC-22 mRNA expression can be induced by TGFβ3 and whether it is involved in or necessary for TGFβ-induced apoptosis. We further show that TSC-22 can enhance TGFβ3-induced Smad response and epithelial cell death. In addition, overexpression of TSC-22 alone can induce a Smad response and apoptosis in mammary epithelial cell cultures, which is independent of p53. Further, we have performed tests to study the necessity for Smad proteins during TSC-22-induced apoptosis, and to establish the intracellular localisation of TSC-22. A pilot study on a small cohort of archival breast cancer cases, representing all stages of malignant progression, shows that TSC-22 protein was reduced or undetectable in 60% of breast carcinomas when compared with adjacent normal breast tissue, suggesting that TSC-22 could indeed be a potential novel tumour suppressor gene. We shall present data showing that methylation of the TSC-22 promoter is not involved in the reduction of TSC-22 protein in breast cancer.