Breast cancer is a highly heterogeneous disease with multiple drivers and a complex regulatory network. Periostin (Postn) is a matricellular protein involved in a plethora of cancer types and other diseases. More specifically, Postn has been shown to be involved in various processes of tumor progression such as angiogenesis, cell survival, invasion, and metastasis. A high Postn level in breast cancer has been corelated with a more aggressive phenotype. Despite extensive research, it remains unclear what Postn is doing to the cancer environment and how cancer cells regulate Postn. Here, we assessed the role and regulation mechanisms of Postn in ErbB2-mediated tumorigenesis. By crossing Postn deficient animals into the oncogenic NeuNDL model of ErbB2-positive breast cancer, we have shown that Postn deletion delays tumor onset and increases overall survival by affecting proliferation and apoptosis. These tumors also showed a decrease in collagen deposition which is the proposed mechanism for its effect in vivo. Using isolated cancer cells from the Postn deficient background we assessed re-expression of Postn which had no effect on in vitro tumorigenesis processes or in vivo subcutaneous growth in immunodeficient mice. Furthermore, we established an in vitro model to study the regulation of Postn using a bovine pituitary gland derived extract as a natural repressor of Postn. Using mass spectrometry and RNA sequencing, we identified potential regulators of Postn gene expression. We also showed a cross regulation between FGFR, TGFβ and PI3K/AKT pathways to regulate Postn expression. In ErbB2-mediated murine breast cancer cells, we found that TGFβ can induce Postn expression in a SMAD-independent manner while bFGF can repress Postn expression through a PKC-dependent pathway. Postn induction and repression by TGFβ and bFGF respectively, are both dependent on PI3K/AKT signaling. Overall, these results suggest a cancer-driving function for Postn and reveal a novel mechanism for regulating Postn expression.
| Identifer | oai:union.ndltd.org:uottawa.ca/oai:ruor.uottawa.ca:10393/42753 |
| Date | 28 September 2021 |
| Creators | Labrèche, Cédrik |
| Contributors | Sabourin, Luc A. |
| Publisher | Université d'Ottawa / University of Ottawa |
| Source Sets | Université d’Ottawa |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | application/pdf |
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