title: Lack of efficacy of the statins atorvastatin and lovastatin in rodent mammary carcinogenesis.
abstract: The statins are highly effective in lowering cholesterol by inhibiting 3-hydroxy-3-methylglutaryl CoA reductase. Recently, there has been conflicting epidemiologic data indicating that statins decrease the incidence of certain types of cancer, including breast cancer. Atorvastatin and lovastatin, statins with different lipophicilities, were administered in diet either as single agents or in combination with suboptimal doses of tamoxifen or the retinoid X receptor agonist bexarotene were evaluated for prevention of estrogen receptor-positive mammary cancers induced in the rat with methylnitrosourea. Atorvastatin (125 or 500 mg/kg diet) alone did not significantly alter cancer incidence or multiplicity. Suboptimal doses of tamoxifen (0.4 mg/kg diet) or bexarotene (80 mg/kg diet) reduced cancer multiplicity from 3.8 (control) to 2.9 and 0.9, respectively. Combining atorvastatin (500 mg/kg diet) with either of these effective agents minimally altered their efficacy. Although this dose of atorvastatin did not decrease serum triglyceride levels in control rats, it significantly decreased triglyceride levels that had been increased in bexarotene-treated rats. Experiments done with a second statin, lovastatin (100 and 400 mg/kg diet), yielded similar results: (a) limited activity when administered alone, (b) no obvious synergy with bexarotene, and (c) an ability to decrease bexarotene-induced increases in serum triglycerides. Thus, the statins had minimal activity in this model of mammary cancer in which approximately half of the cancers are mutated in the Ha Ras oncogene. Similarly, atorvastatin failed to alter the development of estrogen receptor-negative mammary carcinomas in a new animal model using bitransgenic mice (MMTV-Neu(+/-)/p53KO(+/-)), whereas bexarotene (250 mg/kg diet) was effective.
authors.affiliation: Chemopreventive Agent Development Research Group, Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland, USA. lubetr@nih.gov
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Lubet
authors.forename: Daniel
authors.initials: D
authors.lastname: Boring
authors.forename: Vernon E
authors.initials: VE
authors.lastname: Steele
authors.forename: J Michael
authors.initials: JM
authors.lastname: Ruppert
authors.forename: M Margaret
authors.initials: MM
authors.lastname: Juliana
authors.forename: Clinton J
authors.initials: CJ
authors.lastname: Grubbs
mesh_terms: D000477:Alkylating Agents / Q000633:toxicity; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D000069059:Atorvastatin; D000077610:Bexarotene; D049109:Cell Proliferation / Q000187:drug effects; D004032:Diet; D004195:Disease Models, Animal; D005260:Female; D018734:Genes, erbB-2 / Q000502:physiology; D006538:Heptanoic Acids / Q000627:therapeutic use*; D008148:Lovastatin / Q000627:therapeutic use*; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology*; D008770:Methylnitrosourea / Q000633:toxicity; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011758:Pyrroles / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000378:metabolism; D047488:Retinoid X Receptors / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
chemical_list: D000477:Alkylating Agents; D016588:Anticarcinogenic Agents; D000924:Anticholesteremic Agents; D018931:Antineoplastic Agents, Hormonal; D006538:Heptanoic Acids; D011758:Pyrroles; D011960:Receptors, Estrogen; D047488:Retinoid X Receptors; D013764:Tetrahydronaphthalenes; D016159:Tumor Suppressor Protein p53; D013629:Tamoxifen; D008770:Methylnitrosourea; D008148:Lovastatin; D000069059:Atorvastatin; D000077610:Bexarotene