Deregulation of Tropomyosin in Human Breast Cancer

摘要

Tropomyosins (TMs) are actin filament-binding proteins involved in regulating cell motility in non-muscle cells. Expression of high molecular weight (HMW) TM isoforms is down regulated in many oncogene transformed cell lines. HMW TM expression is also frequently reduced in human breast cancer cell (RB CC) lines and invasive tumors; however, the exact identity of these isoforms is unclear. Northern and Western blot analysis with isoform-specific TM reagents demonstrated that normal, mortal and benign, immortalized RBEC express both RMW and LMW TM isoforms. Remarkably, expression of most TM isoforms was reduced or absent in weakly tumorigenic RB CC, whereas they were elevated in highly tumorigenic RB CC. The differences in TM expression resulted from altered RNA (RMW TM isoforms) and protein (LMW TM isoforms) abundance, through altered epigenetic and degradative mechanisms, respectively. Immunohistochemical analysis performed on sections from human breast tumors revealed altered TM expression in 50% of tumors. Reduced TM expression correlated with age at diagnosis (<46 years old; p--O.0279, Fisher's exact test) and negative progesterone receptor (PR) status (p=O.0153, Fisher's exact test). Life table analysis revealed a significant difference in survival between patients with reduced HMW TM expression and those with normal TM expression (chi-square = 4. 505, p = 0.0338). These results suggest that TM expression becomes dysregulated during breast tumorigenesis and that specific TM expression profiles are associated with the invasive and/or malignant potential of breast cancer cells.