We have reported PTP gamma expression was downregulated by 17 beta-estradiol (E2) and Zeranol (Z) and that PTP gamma may function as an estrogen-regulated cancer suppressor in human breast. We utilized RT-PCR to examine expression of estrogen receptor alpha (ER alpha) and beta (ER beta) mRNA in MCF-7 and MDA-MB-231 cells and to investigate the regulation of PTP gamma expression by E2 and Z in the absence or presence of ICI 182,780 (ICI) in both cells, and immunohistochemistry to examine ER alpha and ER beta protein in normal and cancerous human breast. Results show that MCF-7 express both ER alpha and ER beta, and MDA-MB-231 express only ER beta. Both E2 and Z (30 nM; 24 h) suppressed PTP gamma by approximately 56% in MCF-7 cells and these effects were completely blocked by 1 mM of ICI. In contrast, E2, Z and ICI had no effects on PTP gamma expression in MDA-MB-231 cells. Interestingly, both E2 and Z suppressed PTP gamma by approximately 45% in MDA-MB-231 cells transfected with ER alpha, and these effects were completely blocked by 100 nM of ICI. Both RT-PCR and immunohistochemical staining showed that ER alpha expression was significantly higher in cancerous human breast than in normal breast, while ER beta was higher in normal human breast than in cancerous breast. In combination with our previous findings of greater PTP gamma expression levels in normal human breast than cancerous breast, current results show that lower PTP gamma was associated with higher ER alpha in cancerous human breast tissues. In conclusion, results indicate that Z induces estrogenic effects in human breast relative of PTP gamma expression and the estrogenic down-regulation of PTP gamma expression in human breast is associated with ER alpha.