TY - JOUR
T1 - Breast cancer growth prevention by statins
AU - Campbell, Michael J.
AU - Esserman, Laura J.
AU - Zhou, Yamei
AU - Shoemaker, Mark
AU - Lobo, Margaret
AU - Borman, Elizabeth
AU - Baehner, Frederick
AU - Kumar, Anjali S.
AU - Adduci, Kelly
AU - Marx, Corina
AU - Petricoin, Emanuel F.
AU - Liotta, Lance A.
AU - Winters, Mary
AU - Benz, Stephen
AU - Benz, Christopher C.
PY - 2006/9/1
Y1 - 2006/9/1
N2 - 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 κB (NF-κB). Key intermediates regulating cell survival by NF-κB 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-κB 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.
AB - 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 κB (NF-κB). Key intermediates regulating cell survival by NF-κB 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-κB 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.
UR - http://www.scopus.com/inward/record.url?scp=33749040295&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-05-4061
DO - 10.1158/0008-5472.CAN-05-4061
M3 - Article
C2 - 16951186
AN - SCOPUS:33749040295
SN - 0008-5472
VL - 66
SP - 8707
EP - 8714
JO - Cancer Research
JF - Cancer Research
IS - 17
ER -