| Summary: | Thesis (Ph.D.)--Boston University === Each individual breast tumor contains a heterogeneous mix of cancer cells. Recent evidence suggests that the cellular heterogeneity inherent to breast cancer, which underlies metastasis, resistance to treatment and disease recurrence, can be driven by a distinct population of tumor cells referred to as cancer stem cells. However, the extracellular cues and intracellular signaling pathways that cancer stem cells rely on remain largely unknown. The aim of this dissertation was to investigate the functional relevance of tumor cell-derived periostin, a secreted extracellular matrix (ECM) molecule, to cancer stem cells and determine the pathways activated downstream of periostin through the integrin αvβ3 receptor. The rationale for this work was based on correlative evidence that connected periostin and integrin αvβ3 expression to numerous phenotypes associated with cancer stem cells including residence in a cell state associated with epithelial-mesenchymal transition (EMT), mammosphere formation and expression of the CD44+/CD24- surface phenotype. Multiple breast cancer cell lines with knockdown of either periostin or integrin β3 showed characteristics suggestive of a reduced cancer stem cell population such as impaired mammosphere formation and an inability to maintain a subpopulation of aldehyde dehydrogenase (ALDH)-positive cancer cells, implying that this autocrine/paracrine signaling axis is required to maintain breast cancer stem cells. Furthermore, this axis was found to be expressed in a subset of basal-like breast cancer cell lines. Additionally, high periostin expression was associated with a poor prognosis in patients with estrogen receptor (ER)-negative breast cancer. Gene expression analysis revealed that breast cancer cells with knockdown of periostin exhibited significant suppression of a distinct cytokine network, which includes IL-6 and IL-8, two cytokines that have been linked to the regulation of cancer stem cells. In a different cellular context, periostin could regulate the transcription of multiple WNT ligands. Thus, periostin serves as a critical regulator of the cancer stem cell state and acts through integrin signaling to control the production of other secreted factors that can also modulate cancer stem cells. These findings suggest that basal-like breast cancers can establish a microenvironmental niche supportive of cancer stem cells, which might be relevant as a biomarker or therapeutic target.
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