N-(4-Hydroxyphenyl)retinamide is more potent than other phenylretinamides in inhibiting the growth of BRCA1-mutated breast cancer cells.
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.
Simeone
Ann-Marie
AM
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. amsimeon@mdanderson.org
Deng
Chu-Xia
CX
Kelloff
Gary J
GJ
Steele
Vernon E
VE
Johnson
Marcella M
MM
Tari
Ana M
AM
D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D017313:Fenretinide / Q000031:analogs & derivatives / Q000494:pharmacology*; D019398:Genes, BRCA1; D006801:Humans; D009154:Mutation; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
D017313:Fenretinide; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase