title: Resveratrol fuels HER2 and ERα-positive breast cancer behaving as proteasome inhibitor.
abstract: The phytoestrogen resveratrol has been reported to possess cancer chemo-preventive activity on the basis of its effects on tumor cell lines and xenograft or carcinogen-induciblein vivomodels. Here we investigated the effects of resveratrol on spontaneous mammary carcinogenesis using Δ16HER2 mice as HER2+/ERα+ breast cancer model. Instead of inhibiting tumor growth, resveratrol treatment (0.0001% in drinking water; daily intake of 4μg/mouse) shortened tumor latency and enhanced tumor multiplicity in Δ16HER2 mice. Thisin vivotumor-promoting effect of resveratrol was associated with up-regulation of Δ16HER2 and down-regulation of ERα protein levels and was recapitulatedin vitroby murine (CAM6) and human (BT474) tumor cell lines. Our results demonstrate that resveratrol, acting as a proteasome inhibitor, leads to Δ16HER2 accumulation which favors the formation of Δ16HER2/HER3 heterodimers. The consequential activation of downstream mTORC1/p70S6K/4EBP1 pathway triggers cancer growth and proliferation. This study provides evidence that resveratrol mechanism of action (and hence its effects) depends on the intrinsic molecular properties of the cancer model under investigation, exerting a tumor-promoting effect in luminal B breast cancer subtype models.
authors.affiliation: School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, 62032, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Andreani
authors.affiliation: School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, 62032, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Bartolacci
authors.affiliation: School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, 62032, Italy.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Wijnant
authors.affiliation: Department of Biomolecular Sciences, Section of Biochemistry and Molecular Biology, University of Urbino "Carlo Bo", Urbino, 61029, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Crinelli
authors.affiliation: Department of Biomolecular Sciences, Section of Biochemistry and Molecular Biology, University of Urbino "Carlo Bo", Urbino, 61029, Italy.
authors.forename: Marzia
authors.initials: M
authors.lastname: Bianchi
authors.affiliation: Department of Biomolecular Sciences, Section of Biochemistry and Molecular Biology, University of Urbino "Carlo Bo", Urbino, 61029, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Magnani
authors.affiliation: Aging Research Centre, G. d'Annunzio University, Chieti, 66100, Italy.
authors.forename: Albana
authors.initials: A
authors.lastname: Hysi
authors.affiliation: Aging Research Centre, G. d'Annunzio University, Chieti, 66100, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Iezzi
authors.affiliation: School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, 62032, Italy.
authors.forename: Augusto
authors.initials: A
authors.lastname: Amici
authors.affiliation: School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, 62032, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Marchini
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects; D013267:Stilbenes / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D047628:Estrogen Receptor alpha; D061988:Proteasome Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases; D000077185:Resveratrol; D013267:Stilbenes; C524056:Erbb2 protein, mouse
keywords: breast cancer; estrogen receptor; proteasome; resveratrol; Δ16HER2 mice