Breast cancer growth prevention by statins.
Statins are cholesterol-lowering drugs with pleiotropic activities including inhibition of isoprenylation reactions and reduction of signals driving cell proliferation and survival responses. The objectives of this study were to examine the effects of statins on breast cancer cells, both in vitro and in vivo, and to begin to determine their mechanism of action. We evaluated the effects of statins on breast cancer cell growth, phosphoprotein signaling intermediates, survival/apoptosis regulators, cell cycle regulators, and activated transcription factors. We also examined the in vivo effect of statin administration in a mouse ErbB2(+) breast cancer model. Only lipophilic statins had direct anticancer activity in vitro. Breast cancer cells with activated Ras or ErbB2 pathways seemed to be more sensitive than those overexpressing estrogen receptor, and this correlated with endogenous levels of activated nuclear factor kappaB (NF-kappaB). Key intermediates regulating cell survival by NF-kappaB activation, as well as cell proliferation by the mitogen activated protein kinase cascade, were among the earliest phosphoproteins influenced by statin treatment. These early effects were followed by declines in activator protein-1 and NF-kappaB activation and concordant changes in other mediators of proliferation and apoptosis. In vivo results showed that oral dosing of statins significantly inhibited the growth of a mouse mammary carcinoma. Lipophilic statins can exert direct anticancer activity in vitro by reducing proliferation and survival signals in susceptible breast cancer phenotypes. Tumor growth inhibition in vivo using a clinically relevant statin dose also seems to be associated with reduced tumor cell proliferation and survival. These findings provide supporting rationale for future statin trials in breast cancer patients.
Campbell
Michael J
MJ
Department of Surgery, University of California San Francisco/Mt. Zion Medical Center, Room C342, 1600 Divisadero, San Francisco, CA 94115, USA. campbellm@surgery.ucsf.edu
Esserman
Laura J
LJ
Zhou
Yamei
Y
Shoemaker
Mark
M
Lobo
Margaret
M
Borman
Elizabeth
E
Baehner
Frederick
F
Kumar
Anjali S
AS
Adduci
Kelly
K
Marx
Corina
C
Petricoin
Emanuel F
EF
Liotta
Lance A
LA
Winters
Mary
M
Benz
Stephen
S
Benz
Christopher C
CC
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology* / Q000517:prevention & control; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D004273:DNA, Neoplasm / Q000737:chemistry / Q000187:drug effects; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism; D009690:Nucleic Acid Conformation
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D016328:NF-kappa B