Biphasic actions of estrogen on colon cancer cell growth: possible mediation by high- and low-affinity estrogen binding sites

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Abstract
The present experiments were carried out to investigate the possible direct effects of estrogens (E) on the growth of colon cancer cells. Estradiol exhibited a concentration-dependent biphasic growth effect on a mouse colon cancer cell line (MC-26). Low concentrations of estradiol (10−10 m to 10−8 m) had a growth-stimulatory effect, while higher concentrations (10−7 m to 10−6 m) were growth-inhibitory. Estrogen receptor (ER) mRNA as well as specific, saturable binding of estradiol to ER (Kd=0.3nm, Bmax=0.72 fmol/μg DNA) was identified in these cells. In addition to the classical high affinity ER, lower affinity, higher capacity estrogen binding sites (Kd=35mm, Bmax=30 fmol/μg DNA) were also characterized in MC-26 cells. These two types of estrogen binding sites exhibited distinct binding specificities for E and antiestrogens. Treatment of MC-26 cells with an oligodeoxy-nucleotide antisense to the translation start codon of ER mRNA did not alter the grown-inhibitory effect of 10−6 m estradiol, demonstrating that the growth-inhibitory effect of high concentrations of E was not mediated by ER; we have previously shown that under the same conditions, ER antisense oligonucleotides do block the growth-stimulatory effects of 10−9 m E2 in MC-26 cells. The data suggest that physiological concentrations of estradiol acting via the classical ER may have a proliferative effect on the growth of colon cancer cells. However, in situations where there are high luminal concentrations of estrogenic compounds, they may act on low affinity estrogen binding sites that mediate the growth-inhibitory effect.