Pathology - Theses

Permanent URI for this collection

Search Results

Now showing 1 - 1 of 1
  • Item
    Thumbnail Image
    Delineating the tumor suppressive role of Scribble in prostate cancer progression and metastasis
    Borsetti, Yvonne Christine ( 2013)
    Cell and tissue polarity are distinguished by the asymmetrical distribution of cytoplasmic and membrane components that allows the formation of structurally and functionally distinct domains within cells, and the organisation of multilayered tissues. This asymmetry is required for many cellular processes including migration, interaction with the microenvironment, diversification of cell shapes and development. To establish cellular polarity several polarity regulators are required, such as Scribble, whose loss results in deregulated cellular functions. Scribble is localised at the baso-lateral membrane, which is crucial for its normal functionality. Mislocalisation, which appears as diffuse expression within the cytoplasm, also results in disrupted cellular polarity and therefore impacts polarity regulated cellular functions. Scribble is widely accepted as an evolutionarily conserved tumor suppressor that is often deregulated in many human epithelial cancers, and is generally considered to contribute to tumor progression. Loss of cell and tissue polarity is a hallmark of epithelial cancers suggesting a crucial role for polarity regulators in suppressing tumor formation and progression(1). Interestingly, Scribble is also found to be overexpressed in many epithelial cancers, including prostate cancer, while mislocalization in prostate cancer rather than overexpression correlates with poor patient outcome in the clinic. Scribble has been shown to be a weak initiator of prostate neoplasia in mice owing to elevated Ras/MAPK signaling. Furthermore, Scribble depletion and K-Ras-oncogenic activation have been shown to cooperate in vivo, resulting in an increased incidence of invasive prostate carcinoma compared to single mutants, indicating that Scribble loss can contribute to tumor progression in the presence of an additional oncogenic mutation. Nonetheless, the molecular mechanisms underpinning tumour progression in the context of Scribble loss are not well understood. To directly assess the role of Scribble in prostate carcinogensis and metastasis, in vitro functional assessment of PC3 prostate cancer cells expressing constructs to knockdown (shSCRIB7), overexpress (hSCRIB) or mislocalize (SCRIB P305L) Scribble together with in vivo experimental models of metastasis have been performed. This work shows that Scribble is upregulated in PC-3 cells and that Scribble plays a role in coordinating directed cell migration and invasion, but does not mediate PC-3 cell cycle progression or proliferation in vitro. In addition, by employing the well characterized prostate cancer transgenic mouse model (PBCre+;Ptenfl/fl), in combination with Scribble depletion, it appears that loss of Scribble and Pten cooperate to facilitate invasion, associated with a reduction in the cell:cell adhesion molecule E-cadherin. Collectively, these findings establish that Scribble functions to coordinate prostate cancer cell migration and invasion and that deregulation of Scribble (either by over-expression, depletion or mislocalisation) causes aberrant migration and invasion. Further investigations into understanding how Scribble and the polarity network can regulate migration and invasion during prostate cancer on a molecular level may provide valuable insights into the mechanisms behind prostate cancer progression and prove to hold prognostic value in the clinic, as well as identify novel routes of therapeutic intervention.