Genotoxic Mechanism of Tamoxifen in Developing Endometrial Cancer

Abstract

Increased risk of developing endometrial cancers has been observed in women treated with tamoxifen (TAM), a widely used drug for breast cancer therapy and chemoprevention. The carcinogenic effect may be due to genotoxic DNA damage induced by TAM. In fact, TAM-DNA adducts were detected in the endometrium of women treated with this drug. TAM is alpha-hydroxylated by cytochrome P450 3A4 followed by O-sulfonation by hydroxysteroid sulfotransferase, and reacts with guanine residues in DNA, resulting in the formation of alpha-(N2-deoxyguanosinyl)tamoxifen adducts. During this metabolic process, short-lived carbocations are produced at the ethyl moiety of TAM as reactive intermediates. TAM-DNA adducts promote primarily G -->T transversions in mammalian cells. The same mutations have been frequently detected at codon 12 of the K-ras gene in the endometrial tissue of women treated with this drug. TAM-DNA adducts, if not readily repaired, may act as initiators, leading to development of endometrial cancers. The reactivity of TAM metabolites with DNA is inhibited in toremifene, where the hydrogen atom has been replaced by a chlorine atom at the ethyl moiety. Therefore, toremifene may be a safer alternative to TAM. This article describes an overview of the mechanism of TAM-DNA adduct formation, mutagenic events of this adduct, and detection of TAM-DNA adducts in the endometrium of women treated with TAM.

Tamoxifen-Induced Adduct Formation and Cell Stress in Human Endometrial Glands

“…at ASPET Journals on May 12, 2018 dmd.aspetjournals.org sponsible for the tamoxifen-induced lesions in the human endometrium, but the underlying mechanisms are not fully understood (Kim et al, 2004;Shang, 2006). The present study showed that short-term incubation with tamoxifen caused tamoxifen adduct formation and increased expression of the stress proteins GRP78 and activated caspase 3 in the glandular and surface epithelia of human endometrial explants, whereas there was no expression of stress proteins in the stroma.…”

“…In addition, tamoxifen protein adducts have been detected in human liver microsomes (Dehal and Kupfer, 1996). Both DNA adduct formation and estrogenic effects have been suggested as the mechanism by which tamoxifen induces cancer in the human endometrium (Kim et al, 2004;Shang, 2006). Attempts to determine whether tamoxifen therapy can lead to DNA adducts in the human endometrium have yielded conflicting results (Greaves et al, 1993;Hemminki et al, 1996;Carmichael et al, 1999;Shibutani et al, 2000;Sharma et al, 2003b;Beland et al, 2004).…”

Alterations of the K-ras and p53 genes in Tamoxifen-associated endometrial carcinoma

“…TAM may work as a mild tumor promoter by way of its weak estrogenic activity on the endometrium (4). Alternatively, TAM may play an additional role as a tumor initiator via its weak genotoxicant metabolites (5).…”

FORMATION OF TAMOXIFEN-DNA ADDUCTS VIA O-SULFONATION, NOT O-ACETYLATION, OF α-HYDROXYTAMOXIFEN IN RAT AND HUMAN LIVERS

“…Cytochrome P450 converts TAM to ␣-hydroxytamoxifen (␣-OHTAM), N-desmethyltamoxifen (N-desTAM), and 4-hydroxytamoxifen (4-OHTAM) ( Fig. 1) (reviewed by Kim et al, 2004). Tamoxifen N-oxide (TAM N-oxide) is produced from TAM by flavincontaining monooxygenase.…”

“…The cellular mechanism underlying TAM-induced carcinogenesis may be due to its partial estrogenic effect through the estrogen receptors and/or genotoxic damage (reviewed by Kim et al, 2004). Actually, a high level of TAM-DNA adducts produced in the liver of rats (Han and Liehr, 1992;Osborne et al, 1996) initiates the development of hepatocellular carcinomas (Hard et al, 1993).…”