Journal Article

<i>N</i>-(4-Hydroxyphenyl)retinamide is more potent than other phenylretinamides in inhibiting the growth of <i>BRCA1</i>-mutated breast cancer cells

Ann-Marie Simeone, Chu-Xia Deng, Gary J. Kelloff, Vernon E. Steele, Marcella M. Johnson and Ana M. Tari

in Carcinogenesis

Volume 26, issue 5, pages 1000-1007
Published in print May 2005 | ISSN: 0143-3334
Published online February 2005 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgi038
N-(4-Hydroxyphenyl)retinamide is more potent than other phenylretinamides in inhibiting the growth of BRCA1-mutated breast cancer cells

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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.

Keywords: AEC, 3-amino-9-ethyl-carbazole; 2-CPR, N-(2-carboxyphenyl)retinamide; 3-CPR, N-(3-carboxyphenyl)retinamide; 4-CPR, N-(4-carboxyphenyl)retinamide; DMEM/F12, Dulbecco's modified Eagle medium; FBS, fetal bovine serum; 2-HPR, N-(2-hydroxyphenyl)retinamide; 3-HPR, N-(3-hydroxyphenyl)retinamide; 4-HPR, N-(4-hydroxyphenyl)retinamide; 4-MPR, N-(4-methoxyphenyl)retinamide; l-NMMA, NG-monomethyl-l-arginine; NO, nitric oxide; NOS, nitric oxide synthase; PBS, phosphate-buffered saline

Journal Article.  6237 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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