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

ABSTRACT: 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.

SUBMITTER: Palladini A

PROVIDER: S-EPMC5589593 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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

Palladini Arianna A Nicoletti Giordano G Lamolinara Alessia A Dall'Ora Massimiliano M Balboni Tania T Ianzano Marianna L ML Laranga Roberta R Landuzzi Lorena L Giusti Veronica V Ceccarelli Claudio C Santini Donatella D Taffurelli Mario M Di Oto Enrico E Asioli Sofia S Amici Augusto A Pupa Serenella M SM De Giovanni Carla C Tagliabue Elda E Iezzi Manuela M Nanni Patrizia P Lollini Pier-Luigi PL

Oncotarget 20170413 33

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 ves ...[more]

PMID: 28903354

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Project description:BackgroundThe association of DDT (dichlorodiphenyltrichloroethane) with breast cancer is controversial, but animal studies directly linking DDT to risk are lacking. Concerns with DDT reside in its environmental persistence, bioaccumulation in breast adipose tissue, and endocrine-disrupting actions. Whereas most attention has been focused on estrogenic congeners, we tested the cancer-inducing potential of the antiandrogen, p,p´-DDE [1,1-dichloro-2,2-bis(p-chlorophenyl) ethylene], the most prevalent and persistent DDT metabolite.ObjectivesWe aimed to determine whether developmental exposure to p,p´-DDE stored in adipose tissue surrounding the cancer-prone mammary epithelium of MMTV-Neu mice influences tumor development.MethodsFor localized delivery, Elvax 40P pellets containing p,p´-DDE were implanted into the mammary fat pads of prepubertal female mice. We compared mammary tumor development with p,p´-DDE with development in response to its estrogenic isomer, o,p´-DDE [1,1-dichloro-2-(o-chlorophenyl)-2-(p-chlorophenyl) ethylene], and a mixture of both isomers.Resultsp,p´-DDE implants significantly accelerated mammary tumor onset compared with vehicle Elvax implants. o,p´-DDE had similar results, but only at ? 10 months of age. Lipid-adjusted levels of p,p´-DDE in mammary adipose tissue and serum in young mice were within the ranges of human exposure, whereas concentrations in aged mice were low to undetectable. Exposure to a 2:1 ratio of p,p´-DDE:o,p´-DDE did not result in the younger latency observed with the individual isomers.Conclusionsp,p´-DDE exposure at concentrations relevant to human exposure accelerates mammary carcinogenesis in mice, possibly through hormonal and/or other actions. These data suggest that DDE exposure would promote, but not cause, mammary tumorigenesis. Developmental exposure in immature mammary tissue continues to affect tumor onset even after p,p´-DDE levels have declined. Future studies are needed to determine whether early exposure to p,p´-DDE correspondingly predisposes women to early-onset breast cancer.

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

Publications

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

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