Carcinogenesis Advance Access originally published online on February 3, 2005
Carcinogenesis 2005 26(5):1000-1007; doi:10.1093/carcin/bgi038
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Carcinogenesis vol.26 no.5 © Oxford University Press 2005; all rights reserved.
N-(4-Hydroxyphenyl)retinamide is more potent than other phenylretinamides in inhibiting the growth of BRCA1-mutated breast cancer cells
Departments of 1 Experimental Therapeutics and 2 Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA, 3 Genetics of Development and Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892, USA and Divisions of 4 Cancer Treatment and Diagnostics and 5 Cancer Prevention, National Cancer Institute, Bethesda, MD 20892, USA
* To whom correspondence should be addressed Email: amsimeon{at}mdanderson.org
Women with germline mutations in the breast cancer susceptibility gene BRCA1 are at an increased risk of developing breast cancer. The synthetic retinoid N-(4-hydroxyphenyl)retinamide (4-HPR) has been shown to have a clinical chemopreventive activity in patients with premenopausal breast cancer. Since BRCA1 mutations are associated with an early-onset breast cancer, usually before menopause, we hypothesized that 4-HPR may be an effective chemopreventive agent against breast tumors exhibiting BRCA1 mutations. The objective of this study was to determine the effectiveness and mechanisms of action of 4-HPR and its phenylretinamide analogues in BRCA1-mutated breast cancer cells. At clinically relevant doses, 4-HPR induced apoptosis in human (HCC1937) and murine (W0069, W525) BRCA1-mutated breast cancer cells. Among the various phenylretinamides tested, N-(2-carboxyphenyl)retinamide (2-CPR) and 3-CPR significantly inhibited the growth of HCC1937 cells; however, they were not as potent as 4-HPR in this respect. We also determined the mechanisms by which 4-HPR induces apoptosis in BRCA1-mutated breast cancer cells. The extent to which 4-HPR induced apoptosis in BRCA1-mutated cells correlated with the increases in nitric oxide (NO) production and nitric oxide synthase (NOS) II and NOSIII expression. Use of a NOS inhibitor to block NO production suppressed the inhibitory effects of 4-HPR in all cell lines. These in vitro results suggest that 4-HPR may be an effective chemopreventive agent against breast tumors that exhibit BRCA1 mutations because of its ability to induce NO-mediated apoptosis in such tumors.
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