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Elucidating Molecular Mechanisms of ERBB2/Neu-Induced Mammary Tumorigenesis

Landis, Melissa D
http://rave.ohiolink.edu/etdc/view?acc_num=case1134662885

Abstract Details

2006, Doctor of Philosophy, Case Western Reserve University, Pharmacology.
The 15-30% of human breast cancers that have upregulated HER2/ErbB2/Neu are highly aggressive and resistant to traditional treatments, resulting in poor prognosis. To identify novel therapeutic targets, we derived the transcriptomes associated with tumor progression in two independent mouse models of ErbB2/Neu-induced tumorigenesis. From MMTV-Neu mice, we identified 324 candidate genes unique to ErbB2/Neu-induced tumors relative to wild-type mammary glands. A subset of these genes also changed expression levels in preneoplastic mammary glands, indicating a pivotal role early in ErbB2/Neu-initiated tumorigenesis. Downregulation of several known transforming growth factor (TGF)-β target genes in the ErbB2/Neu molecular signature suggested attenuation of the TGF-β signaling cascade in these tumors. Analysis of TGF-β-Receptor-I/ALK5 by western blot and immunohistochemistry confirmed that Smad-dependent TGF-β signaling was inactive in these tumors. Although absent in most of the tumor, colocalization of phosphorylated Smad2 and Activin-Receptor-IB/ALK4 at the tumor periphery suggested functional Activin signaling at the leading edge of these tumors. Collectively, these data indicate intrinsic TGF-β pathway suppression in ErbB2/Neu tumors via loss of TGF-β-Receptor-I/ALK5. Recent studies have shown that pregnancy can accelerate ErbB2/Neu tumor development, inducing a susceptible cell population in MMTV-Neu mammary glands. The stochastic pattern of tumor development in multiparous MMTV-Neu mice suggests additional events are required for ErbB2/Neu oncogenesis. It remains unclear whether such events are genetic or reflective of the dynamic, pregnancy-associated hormonal control of the gland. Bitransgenic mice generated by breeding MMTV-Neu mice with a model of ovarian hyperstimulation developed multifocal mammary tumors in an accelerated, synchronous manner compared to virgin MMTV-Neu animals. This synchrony of tumor development suggests that trophic maintenance of the mammary gland provides the additional events required for tumor formation and maintains the population of cells targeted by ErbB2/Neu for transformation. The synchronous nature of tumor development in this bitransgenic mouse model permitted characterization of a window of commitment to tumorigenesis and subsequent identification of approximately 2800 genes that demonstrate altered expression with oncogenic commitment. Thirty-two of these genes are also changed in the preneoplastic glands of MMTV-Neu mice, suggesting that this subset of genes may be regulated by ErbB2/Neu and/or contribute to early events of ErbB2/Neu-induced tumorigenesis.
Ruth Keri (Advisor)
202 p.
mammary; breast cancer; tumor progression; transgenic mice; erbB2/neu/HER2; transforming growth factor beta; activin; microarray; synchronous tumorigenicity; susceptible cell population; bitransgenic; luteinizing hormone-overexpressing transgenic mice

Recommended Citations

Citations

  • Landis, M. D. (2006). Elucidating Molecular Mechanisms of ERBB2/Neu-Induced Mammary Tumorigenesis [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1134662885

    APA Style (7th edition)

  • Landis, Melissa. Elucidating Molecular Mechanisms of ERBB2/Neu-Induced Mammary Tumorigenesis. 2006. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1134662885.

    MLA Style (8th edition)

  • Landis, Melissa. "Elucidating Molecular Mechanisms of ERBB2/Neu-Induced Mammary Tumorigenesis." Doctoral dissertation, Case Western Reserve University, 2006. http://rave.ohiolink.edu/etdc/view?acc_num=case1134662885

    Chicago Manual of Style (17th edition)

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© 2005, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.