title: Atorvastatin modulates anti-proliferative and pro-proliferative signals in Her2/neu-positive mammary cancer.
abstract: The widely used anticholesterolemic drugs statins decrease the synthesis of cholesterol and the isoprenylation and activity of small G-proteins such as Ras and Rho, the effectors of which are often critical in cell proliferation. Thanks to this property, it has been hypothesized that statins may have anti-tumor activities. We investigated this issue in BALB-neuT mice, which developed Her2/neu-positive mammary cancers with 100% penetrance, and in TUBO cells, a cell line established from these tumors. Contrary to the mammary glands of BALB/c mice, the tumor tissue from BALB-neuT animals had constitutively activated Ras and ERK1/2. These were reduced by the oral administration of atorvastatin, but the statin did not prevent tumor growth in mice nor reduce the proliferation of TUBO cells, although it lowered the activity of mevalonate pathway and Ras/ERK1/2 signaling. By decreasing the mevalonate pathway-derived metabolite geranylgeranyl pyrophosphate and the RhoA/RhoA kinase signaling, atorvastatin activated NF-κB, that sustained cell proliferation. Unexpectedly Her2-positive cells were much more sensitive to the inhibition of RhoA-dependent pathways than to the suppression of Ras-dependent pathways elicited by atorvastatin. Only the simultaneous inhibition of RhoA/RhoA-kinase/NF-κB and Ras/ERK1/2 signaling allowed the statin to decrease tumor cell proliferation. Our study demonstrates that Her2-positive mammary cancers have redundant signals to sustain their proliferation and shows that statins simultaneously reduce the pro-proliferative Ras/ERK1/2 axis and activate the pro-proliferative RhoA/RhoA-kinase/NF-κB axis. The latter event dissipates the antitumor efficacy that may arise from the former one. Only the association of statins and NF-κB-targeted therapies efficiently decreased proliferation of tumor cells.
authors.affiliation: Department of Genetics, Biology and Biochemistry, University of Torino, via Santena 5/bis, 10126, Torino, Italy. chiara.riganti@unito.it
authors.forename: Chiara
authors.initials: C
authors.lastname: Riganti
authors.forename: Hedwige
authors.initials: H
authors.lastname: Pinto
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Bolli
authors.forename: Dimas C
authors.initials: DC
authors.lastname: Belisario
authors.forename: Raffaele A
authors.initials: RA
authors.lastname: Calogero
authors.forename: Amalia
authors.initials: A
authors.lastname: Bosia
authors.forename: Federica
authors.initials: F
authors.lastname: Cavallo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000069059:Atorvastatin; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006538:Heptanoic Acids / Q000627:therapeutic use*; D000960:Hypolipidemic Agents / Q000627:therapeutic use*; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy* / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D048053:Mitogen-Activated Protein Kinase 6 / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000188:drug therapy; D011758:Pyrroles / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D013729:Terpenes; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D000069059:Atorvastatin; D006538:Heptanoic Acids; D000960:Hypolipidemic Agents; D048052:Mitogen-Activated Protein Kinase 3; D048053:Mitogen-Activated Protein Kinase 6; D016328:NF-kappa B; D011758:Pyrroles; D018719:Erb-b2 Receptor Tyrosine Kinases; D013729:Terpenes; D018631:ras Proteins; D020742:rhoA GTP-Binding Protein; C524056:Erbb2 protein, mouse