Abstract
Amplification or mutation of the Her2 oncoantigen in human mammary glands leads to the development of an aggressive breast carcinoma. Several features of this breast carcinoma are reproduced in mammary carcinomas that spontaneously arise in female transgenic mice bearing the activated rat Her2 oncogene under transcriptional control of the mouse mammary tumor virus promoter-BALB-neuT (neuT) mice. We previously demonstrated that carcinoma progression in neuT mice can be prevented by DNA vaccination with RHuT, a plasmid coding for a chimeric rat/human Her2 protein. RHuT vaccination exerts an antitumor effect, mostly mediated by the induction of a strong anti-rat Her2 antibody response. IgG induced by RHuT vaccine mainly acts by blocking Her2 signaling, thus impairing cell cycle progression and inducing apoptosis of cancer cells, but other indirect effector mechanisms could be involved in the antibody-mediated protection. The recruitment of cells with perforin-dependent cytotoxic activity, able to perform antibody-dependent cellular cytotoxicity, has already been investigated. Less is known about the role of the complement system in sustaining antitumor response through complement-dependent cytotoxicity and cellular cytotoxicity in vaccinated mice. This work highlights that the weight of such mechanisms in RHuT-induced cancer protection is different in transplantable versus autochthonous Her2+ tumor models. These results may shed new light on the effector mechanisms involved in antibody-dependent anti-cancer responses, which might be exploited to ameliorate the therapy of Her2+ breast cancer.
Highlights
Introduction published maps and institutional affilThe Her2 (ErbB2) protein belongs to a family of tyrosine kinase receptors that includes four members (ErbB1-4) which, following dimerization, can recognize, with different specificity, ligands of the epidermal growth factor superfamily
Other than the intrinsic abilities of anti-Her2 antibodies in blocking the activation of Her2 signaling pathway [25,37] and inducing apoptosis [28], the antibody-mediated protection afforded by DNA vaccination could be sustained by the cytotoxic mechanisms of antibody-dependent cellular cytotoxicity (ADCC), complementmediated cytotoxicity (CDC), and complement-mediated cellular cytotoxicity (CDCC)
In order to better understand the weight of such effector mechanisms in mediating antitumor protection, we explored the efficacy of RHuT vaccination in perforinand complement-deficient mice
Summary
Introduction published maps and institutional affilThe Her (ErbB2) protein belongs to a family of tyrosine kinase receptors that includes four members (ErbB1-4) which, following dimerization, can recognize, with different specificity, ligands of the epidermal growth factor superfamily. The overexpression or mutation of Her confers a growth advantage to tumor cells by enhancing the PI3K/Akt “survival” and the MAPK “mitogenic” pathways [1], associating the up-regulation of this receptor to a malignant phenotype. Strategies aimed at targeting Her have been developed, and are routinely used in clinics. Among these is the use of synthetic small molecules that inhibit receptor phosphorylation/activation, preventing its downstream signaling [3,4]. Another strategy rests on the administration of trastuzumab and pertuzumab, two monoclonal antibodies (mAbs) that target the extracellular domain of the receptor.
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