Expression of UGT2B7, a glucuronosyltransferase implicated in the inactivation of 4-hydroxyestrone, and in maintaining the activity of retinoic acid, is enhanced in human breast carcinoma in situ, but reduced or abrogated in invasive breast cancer.

J Weisz, M.B., B.Chir.a, SA Gesti, MSa, DA Shearer, BAa, EE Freuenhoffer, MDb, G Clawson, MD, PhDb, MD Green, MSc, TR Tephly, MD, PhDc

Departments of aObstetrics and Gynecology bPathology, Penn. State University College of Medicine, Hershey, PA, cDepartment of Pharmacology, University of Iowa Health Care, Iowa City, IA

Aim: To examine normal and neoplastic human breast tissue for the expression of UGT2B7, a glucuronosyltransferase with two putative "tumor suppressor" functions, the glucuronidation of 4-hydroxyestrone and of retinoic acid (RA). Glucuronidation of 4-hydroxyestrone blocks its oxidation to 3,4-quinone-estrogen, a potentially mutagenic electrophile, while glucuronidation of RA generates beta-retinoyl glucuronide, a potent mediator of retinoid actions important for maintaining epithelia in a differentiated state. Methods and Results: Evidence for the expression of UGT2B7 in normal human breast parenchyma was obtained by RT/PCR and Western/immunoblot and, for its localization in the mammary epithelium, by immunocytochemistry. Marked reduction of UGT2B7 was identified in invasive cancers by immunocytochemistry and confirmed by immunoblot analysis. In enzyme assays, glucuronidation of 4-hydroxyestrone was consistently demonstrable in normal human breast parenchyma, but undetectable in breast cancers. Paradoxically, in some foci of in situ cancers (CIS), UGT2B7 immunostaining was often not only preserved, but even more intense than in normal mammary epithelium. However, at sites of microinvasion, at the periphery of some CIS, immunostaining was reduced. We observed similar enhanced expression in CIS of catechol-O-methyltransferase and RoDH4, that are catecholestrogen inactivating and RA biosynthetic enzymes, respectively, while their expression in invasive cancers was reduced. Conclusions: Reduced expression of genes encoding enzymes important for metabolic inactivation of catecholestrogens and for maintaining tissue levels of RA, is a common characteristic of invasive breast cancers. We postulate that enhanced expression of such genes in CIS serves to limit invasiveness and propose that identifying such genes and their inducers/suppressors may lead to new approaches to arrest and, possibly, to reverse cancer progression.

KEY WORDS: retinoid, catecholestrogen.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Prognostic Markers.