Synergistic Interaction of the Neu Proto-Oncogene Product and Transforming Growth Factor α in the Mammary Epithelium of Transgenic Mice

Muller, William J.; Arteaga, Carlos L.; Muthuswamy, Senthil K.; Siegel, Peter M.; Webster, Marc A.; Cardiff, Robert D.; Meise, Katherine S.; Li, Feng; Halter, Susan A.; Coffey, Robert J.

doi:10.1128/mcb.16.10.5726

Cited by 147HER2/EGFR in Cancer ResearchEstrogen and related hormone effectsTGF-β signaling in diseases

Synergistic Interaction of the Neu Proto-Oncogene Product and Transforming Growth Factor α in the Mammary Epithelium of Transgenic Mice

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Muller, William J., Arteaga, Carlos L., Muthuswamy, Senthil K., Siegel, Peter M., Webster, Marc A., Cardiff, Robert D., Meise, Katherine S., Li, Feng +2 more·1996·Molecular and Cellular Biology

DOI 10.1128/mcb.16.10.5726PMC PMC231573

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Abstract

Transgenic mice expressing either the neu proto-oncogene or transforming growth factor (TGF-alpha) in the mammary epithelium develop spontaneous focal mammary tumors that occur after a long latency. Since the epidermal growth factor receptor (EGFR) and Neu are capable of forming heterodimers that are responsive to EGFR ligands such as TGF-alpha, we examined whether coexpression of TGF-alpha and Neu in mammary epithelium could cooperate to accelerate the onset of mammary tumors. To test this hypothesis, we interbred separate transgenic strains harboring either a mouse mammary tumor virus/TGF-alpha or a mouse mammary tumor virus/neu transgene to generate bitransgenic mice that coexpress TGF-alpha and neu in the mammary epithelium. Female mice coexpressing TGF-alpha and neu developed multifocal mammary tumors which arose after a significantly shorter latency period than either parental strain alone. The development of these mammary tumors was correlated with the tyrosine phosphorylation of Neu and the recruitment of c-Src to the Neu complex. Immunoprecipitation and immunoblot analyses with EGFR- and Neu-specific antisera, however, failed to detect physical complexes of these two receptors. Taken together, these observations suggest that Neu and TGF-alpha cooperate in mammary tumorigenesis through a mechanism involving Neu and EGFR transactivation.

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Mice co-expressing TGFα and Neu in mammary epithelium developed multifocal mammary cancers with significantly shorter latency than those expressing either gene alone.
“In transgenic mouse studies, mice that co-express TGFα and Neu in mammary epithelium developed multifocal mammary cancers that arose after a significantly shorter latency than those expressing either gene alone (Muller et al., 1996).”
From ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics (2014) · cites this paper as Muller et al., 1996

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Authors: Muller, W. J., Arteaga, C. L., Muthuswamy, S. K., Siegel, P. M., Webster, M. A., Cardiff, R. D., Meise, K. S., Li, F., Halter, S. A., & Coffey, R. J.
Affiliations: McMaster University (CA)
Vanderbilt University (US)
University of California, Davis (US)
ORCID: Muller, William J.
Arteaga, Carlos L.
Muthuswamy, Senthil K.
Siegel, Peter M.
Cardiff, Robert D.
Li, Feng
Coffey, Robert J.
Venue: Molecular and Cellular Biology
Publisher: Informa UK Limited
Published: 1996-10
Volume: 16
Issue: 10
Pages: 5726-5736
ISSN: 0270-7306 (ISSN-L)
1098-5549
DOI: 10.1128/mcb.16.10.5726
PMC: PMC231573
OpenAlex: W2107921263
Cited by: 147
References: 38
Citations by year: 2026: 2 · 2024: 1 · 2023: 5 · 2022: 1 · 2021: 2 · 2020: 2 · 2019: 2 · 2018: 1 · 2017: 2 · 2016: 2 · 2015: 3 · 2014: 7 · 2013: 6 · 2012: 3
FWCI: 3.59
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: journals.asm.org/non-commercial-tdm-license (tdm)
Locations: Molecular and Cellular Biology (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
TSpace (University of Toronto) (submittedVersion)
Funders: U.S. Department of Veterans Affairs
Cancer Research Society
Medical Research Council Canada
Medical Research Council
National Cancer Institute (R01 CAS4285, CA46413, R01CA046413)
Topics: Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
Keywords: transforming growth factor-alpha, epidermal growth factor receptor, mammary tumors, mammary epithelium, tumor latency, receptor tyrosine phosphorylation, Src kinase, receptor transactivation, heterodimerization, bitransgenic mice, oncogene cooperation
MeSH terms: Aging, Animals, Cell Transformation, Neoplastic, Epithelium, Female, Mammary Glands, Animal, Mammary Tumor Virus, Mouse, Mammary Neoplasms, Experimental, Mice, Transgenic, Phosphorylation, Transcription, Genetic, Transforming Growth Factor alpha, Erb-b2 Receptor Tyrosine Kinases, Genes, erbB-2, Dimerization, Mice

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Synergistic Interaction of the Neu Proto-Oncogene Product and Transforming Growth Factor α in the Mammary Epithelium of Transgenic Mice

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