Background: Com-1 is a molecule that has recently discovered to have putative action on the metastatic nature of cancer cells. The current study investigated the impact of Com-1 on oestrogen regulated cell growth of breast cancer cells and explored the potential link between Com-1 and ER-beta. Method: Full length Com-1 cDNA was isolated from normal mammary tissues. Ribozyme transgenes that specifically targeted human Com-1 were constructed using the pEF6/V5-His vector. Expression of Com-1 was assessed at both mRNA and protein levels. Interaction of Com-1 with other candidate molecules was studied using immunoprecipitation and Western blotting. Results: Elimination of Com-1 by way of ribozyme transgenes results in breast cancer cells with increased rate of growth and increased invasive potential. In contrast, over-expression of Com-1 in the cancer cells had an opposite effect. In ER-alpha-negative/ER-beta positive MDA MB-231 cells, elimination of Com-1 caused more vigorous growth in response to 17-beta-estradiol. However, the effect of Com-1 modification on MCF-7, which is positive for both ER-alpha and ER-beta, was less clear. Protein interaction analysis has indicated that the Com-1 and ER-beta were mutually co-precipitated with each other in breast cancer cells. Immunocytochemical staining revealed that Com-1 was primarily present in the nucleus, with some degree of cytoplasmic staining, and that the distribution of Com-1 was identical to that of ER-beta. 17-beta-Estradiol stimulation resulted in reduction of nucleic staining of Com-1. This reduction of nucleic Com-1 can be reverted when ubiquitin inhibitor, ubiquitin aldehyde or the lactacystin proteosome inhibitor was present, suggesting a pivotal role of the ubiquitin-proteo some pathway in the Com-1/ER-beta complex. Conclusion: Com-1 plays a tumour suppressor role in breast cancer cells and is involved in oestrogen-regulated cell growth. This action is potentially exerted by interacting with ER-P, in human breast cancer cells. The fate of Com-1 can be dually regulated by oestrogen and ubiquitin pathway. (c) 2005 Elsevier Inc. All rights reserved.