The ErbB-2/neu receptor tyrosine kinase is involved in normal tissue development. However, this receptor has been implicated in the genesis of human breast and renal carcinomas, where ErbB2 is amplified in 20--30% of human breast cancers and correlates with poor prognosis. Using the non-transformed MDCK epithelial cell model, I have established that a deregulated activated ErbB2/Neu receptor (NeuNT) but not overexpression of the wild type (WT) receptor induces cell dispersal and motility, accompanied by the breakdown of cell-cell junctions and E-cadherin internalization, in addition to reorganization of the actin cytoskeleton. This phenotype can be reversed following treatment of the cells with a pharmacological inhibitor of MEK, indicating that MEK dependent pathways are involved in the NeuNT-induced remodeling of cell-cell junctions. In three-dimensional cultures of MDCK cells, NeuNT but not WT ErbB2 triggers a morphogenic response that correlates with recruitment and increased phosphorylation levels of the Shc adapter protein. This demonstrates that the deregulated ErbB2/NT receptor induces a distinct biological response when compared to the wild type receptor and induces the loss of epithelial architecture observed in carcinomas. / Invasive morphogenesis downstream from the Met/HGF receptor is modulated through a sustained phosphorylation of the Gab1 docking protein and of downstream kinase (Erk). In contrast, a transient phosphorylation of Gab1 and Erk induced by EGF is not sufficient to promote a morphogenic response. In Chapter III, I demonstrate that NeuNT but not the WT ErbB2 receptor display elevated and sustained levels of Gab1 and Erk phosphorylation which correlates with their ability to promote invasive morphogenesis. In addition, co-immunoprecipitation analyses provide evidence for the recruitment of Gab1 to ErbB2/Neu in a Grb2-dependent and Grb2-independent manner. / To identify physiologically relevant factors that synergize with ErbB2, I established that HGF, the Met receptor ligand, promotes the disruption and invasion of NeuNT-induced epithelial structures in three dimensional matrix cultures. Moreover HGF synergizes with NeuNT, enhancing the invasive potential of NeuNT expressing cells ten fold through Matrigel. HGF treatment of NeuNT expressing cells promotes a decrease in E-cadherin protein, and can be blocked or reversed by treatment with the MEK inhibitor, UO126, establishing the involvement of MEK-dependent pathways in this process. These results demonstrate that physiological signals downstream from HGF/Met cooperate with deregulated ErbB2/Neu to enhance the malignant phenotype promoting a more stable epithelial-mesenchymal transition and enhanced cell invasion.

Pancreatic cancer is considered the fifth leading cause of cancer deaths in Canada and one of the most fatal diseases in the world. Its definite underlying cause is still unidentified, and its actual cell of origin remains unclear. Unfortunately, most of the current research on the pancreas is focused on one disease only, namely diabetes with much less consideration for other pancreatic diseases. Diabetes has been extensively studied from a developmental aspect, and continues to attract the interest of numerous researchers. On the contrary, few accomplishments have been done to decode the developmental errors occurring in pancreatic cancer. It is therefore necessary to allocate more research resources to address this disease from a developmental aspect. / This study provides a literature review of the pancreas concerning its anatomy and function, transcription factors and signaling pathways controlling its development, and the role of these signaling pathways in pancreatic cancer. The review provides distinct emphasis on three important aspects. First, a review of pancreas development is provided, with a focus on different transcription factors and signaling pathways involved in this process. Second, it addresses how the signaling pathways which play a role in pancreas development are the same signaling pathways that play a role in pancreatic cancer, additional emphasis is placed on describing the genetic alterations occurring in pancreatic cancer. Third, a methodology of approaching pancreatic cancer research from a developmental aspect is presented. Using an example of one gene, Anterior gradient 2 (Agr2), is highly expressed in pancreatic cancer in ductal cells only, and might play a role in ductal cell development of the pancreas. Thus, the main objective of this review is to provide a developmental framework for the analysis of pancreatic cancer.

Prolactin is a key mammary gland differentiation factor. However, the contribution of prolactin (PRL) to breast carcinogenesis is less clear. Accumulating evidences indicate that in established breast carcinomas autocrine/paracrine PRL can enhance growth/viability of breast cancer cells. Still, it is not known whether the ascribed pro-oncogenic activity of PRL describes fully the role of PRL in regulating breast carcinogenesis. On the other hand a critical role for Ras-Erk1/2 and TGF-beta (Transforming Growth Factor beta) pathway in breast cancer progression has already been established. Our results indicate that blocking PRL signal leads to activation of Ras-Erk1/2 pathway and TGF-beta pathway, two key pathways contributing to breast cancer metastasis. I showed that modulation of PRL signaling in breast cancer cells alters their morphogenic program. My results highlight a critical role for PRL in regulating epithelial plasticity and implicate PRL as invasive suppressor hormone in breast cancer cells.

Prostate carcinoma (CaP) is the most frequently diagnosed malignancy in men in Western countries. Increased activity of the androgen receptor (AR) and/or AR gene (AR) amplification in the majority of both androgen-dependent and androgen-independent prostate cancers suggest that the AR plays an important role in CaP. / The polymorphic AR CAGn, repeat correlates inversely with AR transactivation. To better understand the contribution of this repeat to CaP, we propose to replace the stable mouse AR CAG/CAA/CAC tract with various lengths of CAG, using gene knock-in methodology. The neo-NTR-HSV-tk cassette from the pPGKneoNTRtkpA vector was introduced into the ploxPneo-1 vector such that loxP sites flanked it. Various CAG repeats were then cloned into mouse AR genomic 5' end clone. Finally, the 5' and 3' mouse AR genomic DNA fragments were cloned into the targeting vector, upstream and downstream of the cassette with flanking loxP sites. Knock-in mice with various CAG repeat lengths will be generated using these constructs.

Thesis (Ph.D.)--Pacific Graduate School of Psychology, 1999. / Source: Dissertation Abstracts International, Volume: 60-05, Section: B, page: 2338. Chair: Catherine Classen.

Thesis (M.D.)--University of New South Wales, 2001. / Also available online.

Thesis (Ph.D.)--University of California, San Francisco, 2008. / Source: Dissertation Abstracts International, Volume: 69-02, Section: B, page: 0841. Adviser: Allan Balmain.

Thesis (Ph.D.)--University of California, San Francisco with the University of California, Berkeley, 2008. / Source: Dissertation Abstracts International, Volume: 69-06, Section: B, page: 3693. Adviser: Daniel Fletcher.

Thesis (Ph.D.)--University of California, San Francisco, 2006. / Source: Dissertation Abstracts International, Volume: 67-08, Section: B, page: 4197. Adviser: Zena Werb.

Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 2008. / Source: Dissertation Abstracts International, Volume: 69-11, Section: B, page: 6636. Adviser: Eric Oldfield. Includes bibliographical references. Available on microfilm from Pro Quest Information and Learning.