Insulin-like growth factor-1 and 17β-estradiol down-regulate prostate apoptosis response-4 expression in MCF-7 breast cancer cells

• Published in: International journal of molecular medicine Vol. 28; no. 3; pp. 337 - 342
• Main Authors: Casolari, Debora, Pereira, Michelly, de Bessa Garcia, Simone, Nagai, Maria
• Format: Journal Article
• Language: English
• Published: Greece D.A. Spandidos 01-09-2011
• Subjects: Apoptosis - drug effects; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Blotting, Western; Breast Neoplasms - metabolism; Cell Line, Tumor; Cell Proliferation; Down-Regulation; Estradiol - pharmacology; Female; Gene Expression Regulation, Neoplastic; Humans; Insulin-Like Growth Factor I - pharmacology; Polymerase Chain Reaction
• ISSN: 1107-3756; 1791-244X
• DOI: 10.3892/ijmm.2011.691

The PKC apoptosis WT1 regulator gene, also named prostate apoptosis response-4
(PAR-4), encodes a pro-apoptotic protein that sensitizes cells to numerous apoptotic
stimuli. Insulin-like growth factor-1 (IGF-1) and 17β-estradiol (E2), two important
factors for breast cancer development and progression, have been shown to down-regulate
PAR-4 expression and inhibit apoptosis induced by PAR-4 in neuronal cells. In
this study, we sought to investigate the mechanisms of regulation of PAR-4 gene
expression in MCF-7 cells treated with E2 or IGF-1. E2 (10 nM) and IGF-1 (12.5 nM)
each down-regulated PAR-4 expression in MCF-7 cells after 24 h of treatment. The
effect of E2 was dependent on ER activation, as demonstrated by an increase in
PAR-4 expression when cells were pretreated for 1 h with 1 µM ICI-182,780 (ICI)
before receiving E2 plus ICI. The effect of IGF-1 was abolished by pre-treatment
for 1 h with 30 µM LY294002 (a specific PI3-K inhibitor), and significantly inhibited
by 30 µM SB202190 (a specific p38MAPK inhibitor). We also demonstrated that E2
acts synergistically with IGF-1, resulting in greater down-regulation of PAR-4
mRNA expression compared with E2 or IGF-1 alone. Our results show for the first
time that E2 and IGF-1 inhibit PAR-4 gene expression in MCF-7 cells, suggesting
that this down-regulation may provide a selective advantage for breast cancer
cell survival.