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dc.contributor.authorLandis, M. D.
dc.contributor.authorSeachrist, D. D.
dc.contributor.authorAbdul-Karim, F. W.
dc.contributor.authorKeri, R. A.
dc.date.accessioned2009-05-20T10:30:35Z
dc.date.available2009-05-20T10:30:35Z
dc.date.issued2006-06-01
dc.identifier.citationOncogene 2006, 25 (23):3325-3334en
dc.identifier.issn0950-9232
dc.identifier.pmid16434967
dc.identifier.doi10.1038/sj.onc.1209365
dc.identifier.urihttp://hdl.handle.net/10146/68618
dc.descriptionKEYWORDS - CLASSIFICATION: analysis;Animals;Cell Transformation,Neoplastic;Female;genetics;lifestyle modulation of cancer & cancer biomarkers;metabolism;Male;Mammary Glands,Animal;Mammary Neoplasms,Experimental;mechanisms of carcinogenesis;Mice;Mice,Transgenic;pathology;physiology;Pregnancy;Pregnancy Complications,Neoplastic;Receptor,erbB-2;Research.en
dc.description.abstractEpidemiological studies indicate that parity enhances HER2/ErbB2/Neu-induced breast tumorigenesis. Furthermore, recent studies using multiparous, ErbB2/Neu-overexpressing mouse mammary tumor virus (MMTV-Neu) mice have shown that parity induces a population of cells that are targeted for ErbB2/Neu-induced transformation. Although parity accelerates mammary tumorigenesis, the pattern of tumor development in multiparous MMTV-Neu mice remains stochastic, suggesting that additional events are required for ErbB2/Neu to cause mammary tumors. Whether such events are genetic in nature or reflective of the dynamic hormonal control of the gland that occurs with pregnancy remains unclear. We postulated that young age at pregnancy initiation or chronic trophic maintenance of mammary epithelial cells might provide a cellular environment that significantly increases susceptibility to ErbB2/Neu-induced tumorigenesis. MMTV-Neu mice that were maintained pregnant or lactating beginning at 3 weeks of age demonstrated accelerated tumorigenesis, but this process was still stochastic, indicating that early pregnancy does not provide the requisite events of tumorigenesis. However, bitransgenic mice that were generated by breeding MMTV-Neu mice with a luteinizing hormone-overexpressing mouse model of ovarian hyperstimulation developed multifocal mammary tumors in an accelerated, synchronous manner compared to virgin MMTV-Neu animals. This synchrony of tumor development in the bitransgenic mice suggests that trophic maintenance of the mammary gland provides the additional events required for tumor formation and maintains the population of cells that are targeted by ErbB2/Neu for transformation. Both the synchrony of tumor appearance and the ability to characterize a window of commitment by ovariectomy/palpation studies permitted microarray analysis to evaluate changes in gene expression over a defined timeline that spans the progression from normal to preneoplastic mammary tissue. These approaches led to identification of several candidate genes whose expression changes in the mammary gland with commitment to ErbB2/Neu-induced tumorigenesis, suggesting that they may either be regulated by ErbB2/Neu and/or contribute to tumor formation.
dc.language.isoenen
dc.relation.urlhttp://www.nature.com/onc/journal/v25/n23/abs/1209365a.htmlen
dc.relation.urlhttp://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16434967en
dc.subjectGene expression profilingen
dc.subjectErbB2/Neu/HER2en
dc.subjectTransgenic miceen
dc.subjectParityen
dc.subjectBreast canceren
dc.subjectMammary glanden
dc.subject.meshAnimals
dc.subject.meshCell Transformation, Neoplastic
dc.subject.meshFemale
dc.subject.meshMale
dc.subject.meshMammary Glands, Animal
dc.subject.meshMammary Neoplasms, Experimental
dc.subject.meshMice
dc.subject.meshMice, Transgenic
dc.subject.meshPregnancy
dc.subject.meshPregnancy Complications, Neoplastic
dc.subject.meshReceptor, erbB-2
dc.titleSustained trophism of the mammary gland is sufficient to accelerate and synchronize development of ErbB2/Neu-induced tumors.en
dc.typeArticleen
dc.identifier.journalOncogeneen
html.description.abstractEpidemiological studies indicate that parity enhances HER2/ErbB2/Neu-induced breast tumorigenesis. Furthermore, recent studies using multiparous, ErbB2/Neu-overexpressing mouse mammary tumor virus (MMTV-Neu) mice have shown that parity induces a population of cells that are targeted for ErbB2/Neu-induced transformation. Although parity accelerates mammary tumorigenesis, the pattern of tumor development in multiparous MMTV-Neu mice remains stochastic, suggesting that additional events are required for ErbB2/Neu to cause mammary tumors. Whether such events are genetic in nature or reflective of the dynamic hormonal control of the gland that occurs with pregnancy remains unclear. We postulated that young age at pregnancy initiation or chronic trophic maintenance of mammary epithelial cells might provide a cellular environment that significantly increases susceptibility to ErbB2/Neu-induced tumorigenesis. MMTV-Neu mice that were maintained pregnant or lactating beginning at 3 weeks of age demonstrated accelerated tumorigenesis, but this process was still stochastic, indicating that early pregnancy does not provide the requisite events of tumorigenesis. However, bitransgenic mice that were generated by breeding MMTV-Neu mice with a luteinizing hormone-overexpressing mouse model of ovarian hyperstimulation developed multifocal mammary tumors in an accelerated, synchronous manner compared to virgin MMTV-Neu animals. This synchrony of tumor development in the bitransgenic mice suggests that trophic maintenance of the mammary gland provides the additional events required for tumor formation and maintains the population of cells that are targeted by ErbB2/Neu for transformation. Both the synchrony of tumor appearance and the ability to characterize a window of commitment by ovariectomy/palpation studies permitted microarray analysis to evaluate changes in gene expression over a defined timeline that spans the progression from normal to preneoplastic mammary tissue. These approaches led to identification of several candidate genes whose expression changes in the mammary gland with commitment to ErbB2/Neu-induced tumorigenesis, suggesting that they may either be regulated by ErbB2/Neu and/or contribute to tumor formation.


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