Tamoxifen and Estrogen Induce Chromosome Breaks in DNA Repair-Deficient Cells

Shinya Shibutani, Ph.D.
State University of New York at Stony Brook
R01ES09418

Background: Tamoxifen is widely used as an antiestrogen therapy for breast cancer patients and as a chemopreventive agent for healthy women at high risk for breast cancer. Highlighting the complexity of its actions, tamoxifen use has been associated with increased incidence of endometrial cancer in humans and has been shown to cause liver cancer in laboratory animals. It has been characterized as a human carcinogen by the International Agency for Research on Cancer.

The estrogen derivative, 17-estradiol (E2) also possesses carcinogenic activity. Research has suggested that tamoxifen and E2 may be carcinogenic through tumor initiation or promotion. Both agents bind to the estrogen receptor which regulates specific genes. Tamoxifen and 4-hydroxyestradiol, a metabolite of E2, readily form DNA adducts. However, the contribution of these adducts to the carcinogenic potential of both agents remains unclear.

Advance: Using a cell culture system deficient in DNA repair pathways, the NIEHS-supported team explored the molecular mechanism of tamoxifen-induced mutagenesis. The cells were found to be hypersensitive to tamoxifen exhibiting an increase in chromosomal breaks were also sensitive to 4-hydroxyestradiol. The researchers determined that the major deficient DNA repair mechanism responsible for these effects was a process known as translesion DNA synthesis.

Implication: These results combined with previous results from this laboratory indicate that this cell system is a reliable model for analysis of the genotoxicity of estrogen or tamoxifen-related products. Furthermore, the model might prove useful for characterization of the potential mutagenic activities of other agents that induce DNA replication damage and blocks. The researchers conclude that "[a] better understanding of tamoxifen-dependent mutagenesis may contribute to development of new drugs for the treatment or prevention of breast cancer with higher therapeutic efficacy and reduced genotoxicity."

Citation: Mizutani A, Okada T, Shibutani S, Sonoda E, Hochegger H, Nishigori C, Miyachi Y, Takeda S, Yamazoe M. Extensive chromosomal breaks are induced by tamoxifen and estrogen in DNA repair-deficient cells. Cancer Res. 2004 May 1;64(9):3144-7.