One of highly pathogenic
breast cancer cell types are the triple negative (negative in the expression of
estrogen,
progesterone, and ERBB2 receptors)
breast cancer cells. These cells are highly motile and metastatic and are characterized by high levels of the
metastasis regulator
protein SLUG. Using isogenic
breast cancer cell systems we have shown here that high motility of these cells is directly correlated with the levels of the SLUG in these cells. Because epithelial/mesenchymal cell motility is known to be negatively regulated by the
catenin protein plakoglobin, we postulated that the transcriptional repressor
protein SLUG increases the motility of the aggressive
breast cancer cells through the knockdown of the transcription of the
plakoglobin gene. We found that SLUG inhibits the expression of
plakoglobin gene directly in these cells. Overexpression of SLUG in the SLUG-deficient
cancer cells significantly decreased the levels of
mRNA and
protein of
plakoglobin. On the contrary, knockdown of SLUG in SLUG-high
cancer cells elevated the levels of
plakoglobin. Blocking of SLUG function with a
double-stranded DNA decoy that competes with the E2-box binding of SLUG also increased the levels of
plakoglobin mRNA,
protein, and promoter activity in the SLUG-high
triple negative breast cancer cells. Overexpression of SLUG in the SLUG-deficient cells elevated the motility of these cells. Knockdown of
plakoglobin in these low motility non-invasive
breast cancer cells rearranged the actin filaments and increased the motility of these cells. Forced expression of
plakoglobin in SLUG-high cells had the reverse effects on cellular motility. This study thus implicates SLUG-induced repression of
plakoglobin as a motility determinant in highly disseminating
breast cancer.