Nuclear localization of catechol-O-methyltransferase in neoplastic and nonneoplastic mammary epithelial cells

Catechol-O-methyltransferase (COMT) plays both a regulatory and protective role in catechol homeostasis. It contributes to the regulation of tissue le vels of catecholamines and catecholestrogens (CEs) and, by blocking oxidati ve metabolism of catechols, prevents endogenous and exogenous catechols fro m becoming a source of potentially mutagenic electrophiles. Evidence implic ating CEs in carcinogenesis, in particular in the hamster kidney model of e strogen-induced cancer, has focused attention on the protective role of COM T in estrogen target tissues. We have previously reported that treating ham sters with estrogens causes translocation of COMT to nuclei of epithelial c ells in the renal cortex, the site of CE biosynthesis and where the cancers arise, This ending suggested that nuclear COMT may be a marker of a threat to the genome by catechols, including CEs. It is postulated that CEs play a role in the genesis of breast cancer by contributing to a state of chroni c oxidative stress that is presumed to underlie the high incidence of this disease in the United States. Therefore, here we used immunocytochemistry t o re-examine human breast parenchyma for nuclear COMT, In addition to confi rming previous reports of cytoplasmic COMT in mammary epithelial cells, we identified nuclear COMT in foci of mammary epithelial cells in histological ly normal breast tissue of virtually all control (macromastia) and cancer p atients and in breast can-cer cells. There was no correlation between tissu e histology and the numbers of cells with nuclear COMT, the size of foci co ntaining such cells, or intensity of nuclear COMT immunostaining, The focal nature of the phenomenon suggests that nuclear COMT does not serve a house keeping function but that it reflects a protective response to an increased local catechol load, presumably of CEs and, as such, that it may be a char acteristic of the population of women studied who share the same major risk factor for developing breast cancer, that of living in the industrialized West.