HER2 isoforms co-expression differently tunes mammary tumor phenotypes affecting onset, vasculature and therapeutic response.

Autor:	Palladini A; Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy., Nicoletti G; Rizzoli Orthopedic Institute, Laboratory of Experimental Oncology, Bologna, Italy., Lamolinara A; Aging Research Centre, 'Gabriele d'Annunzio' University, Chieti, Italy., Dall'Ora M; Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy., Balboni T; Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy., Ianzano ML; Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy., Laranga R; Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy., Landuzzi L; Rizzoli Orthopedic Institute, Laboratory of Experimental Oncology, Bologna, Italy., Giusti V; Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy., Ceccarelli C; Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.; Pathology Unit, Policlinico S.Orsola-Malpighi University Hospital, Bologna, Italy., Santini D; Pathology Unit, Policlinico S.Orsola-Malpighi University Hospital, Bologna, Italy., Taffurelli M; Department of Medical and Surgical Sciences of Bologna, Bologna, Italy., Di Oto E; Anatomic Pathology, Department of Biomedical and Neuromotor Sciences, Bellaria Hospital, University of Bologna, Bologna, Italy., Asioli S; Anatomic Pathology, Department of Biomedical and Neuromotor Sciences, Bellaria Hospital, University of Bologna, Bologna, Italy., Amici A; University of Camerino, Camerino, Italy., Pupa SM; Istituto Nazionale Tumori, Milano, Italy., De Giovanni C; Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy., Tagliabue E; Istituto Nazionale Tumori, Milano, Italy., Iezzi M; Aging Research Centre, 'Gabriele d'Annunzio' University, Chieti, Italy., Nanni P; Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy., Lollini PL; Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.
Jazyk:	angličtina
Zdroj:	Oncotarget [Oncotarget] 2017 Apr 13; Vol. 8 (33), pp. 54444-54458. Date of Electronic Publication: 2017 Apr 13 (Print Publication: 2017).
DOI:	10.18632/oncotarget.17088
Abstrakt:	Full-length HER2 oncoprotein and splice variant Delta16 are co-expressed in human breast cancer. We studied their interaction in hybrid transgenic mice bearing human full-length HER2 and Delta16 (F1 HER2/Delta16) in comparison to parental HER2 and Delta16 transgenic mice. Mammary carcinomas onset was faster in F1 HER2/Delta16 and Delta16 than in HER2 mice, however tumor growth was slower, and metastatic spread was comparable in all transgenic mice. Full-length HER2 tumors contained few large vessels or vascular lacunae , whereas Delta16 tumors presented a more regular vascularization with numerous endothelium-lined small vessels. Delta16-expressing tumors showed a higher accumulation of i.v . injected doxorubicin than tumors expressing full-length HER2. F1 HER2/Delta16 tumors with high full-length HER2 expression made few large vessels, whereas tumors with low full-length HER2 and high Delta16 contained numerous small vessels and expressed higher levels of VEGF and VEGFR2. Trastuzumab strongly inhibited tumor onset in F1 HER2/Delta16 and Delta16 mice, but not in full-length HER2 mice. Addiction of F1 tumors to Delta16 was also shown by long-term stability of Delta16 levels during serial transplants, in contrast full-length HER2 levels underwent wide fluctuations. In conclusion, full-length HER2 leads to a faster tumor growth and to an irregular vascularization, whereas Delta16 leads to a faster tumor onset, with more regular vessels, which in turn could better transport cytotoxic drugs within the tumor, and to a higher sensitivity to targeted therapeutic agents. F1 HER2/Delta16 mice are a new immunocompetent mouse model, complementary to patient-derived xenografts, for studies of mammary carcinoma onset, prevention and therapy. Competing Interests: CONFLICTS OF INTEREST The authors disclose no potential conflicts of interest
Databáze:	MEDLINE
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