Sir Peter MacCallum Department of Oncology - Theses
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ItemThe role of Pim-1 in breast cancer metastasis( 2017)Breast cancer is the most common cancer in women. Despite advances in treatment options, the spread of breast cancer to distant organs (metastasis) remains the major cause of morbidity and mortality in breast cancer patients. This is attributed primarily to the impairment of function in affected organs. Thus, there remains a vital need for better-targeted treatments that more effectively inhibit the development or progression of metastases. Pim-1 is a serine/threonine survival kinase that has been implicated in the development of metastasis in several haematological and solid cancers. However, little is known about its role in breast cancer. In our laboratory, we previously identified Pim-1 as upregulated in brain metastatic 4T1Br4 syngeneic mouse cells and tumours compared to parental 4T1 cells. This led us to propose that Pim-1 may play a role in mediating breast cancer brain metastasis. Therefore, the overall objective of this project was to examine the expression and functional role of Pim-1 in breast cancer metastasis, with a focus on organ-specific metastasis. We interrogated public databases to show that Pim-1 expression is low to absent in normal breast tissue and increased in breast tumour tissue. Furthermore we show that the murine (4T1Br4) and human (MDA-MB-231Br) brain metastatic breast cancer cell lines and tumours demonstrate the highest expression of Pim-1 mRNA and protein. To investigate the function of Pim-1 in breast cancer metastasis we tested the impact of inhibiting Pim-1, either by gene knock down using short hairpin RNAs or the pharmacological inhibitor SGI-1776, on the ability of 4T1Br4 and MDA-MB-231Br cells to migrate and invade in vitro. 4T1Br4 cells displayed increased migration and invasion propensity after Pim-1 knock down and this was coupled with a decrease in β4 integrin expression. Conversely, MDA-MB-231Br cells showed a decreased ability to migrate and invade after Pim-1 KD, as well as decreased cell surface expression of β1 and β3 integrins. Treatment with SGI-1776 dose-dependently decreased the ability of both 4T1Br4 and MDA-MB-231Br cells to migrate and invade, decreased cell surface expression of β3 integrin in 4T1Br4 cells, and both β1 and β3 integrins in MDA-MB-231Br cells. To examine the effect of Pim-1 inhibition in vivo, we assessed the metastatic spread of Pim-1 knock down MDA-MB-231Br cells in an experimental metastasis assay. After intracardiac injection of Pim-1 knock down cells, we observed a reduction in the number of circulating tumour cells and decreased bone metastasis, indicating a functional role for Pim-1 in breast cancer metastasis to the bone. Data from brain metastasis in this model were inconclusive. In summary, results from this project highlight the importance of Pim-1 in breast cancer metastasis and provide evidence that Pim-1 contributes to the migration and invasion of breast cancer cells both in vitro and in vivo, possibly via regulation of integrin expression, and indicate that Pim-1 is a relevant therapeutic target for the treatment of metastatic breast cancer.
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ItemAn investigation of type-1 interferon and the immune response against breast cancer metastasis( 2016)Breast cancer is a highly prevalent disease that, like many cancers, lacks effective therapies aimed at treating and preventing metastasis. Harnessing the host immune system to recognise and eliminate malignant cells has recently emerged as an effective therapeutic strategy in many cancers. However, response rates to these approved immunotherapies remain modest in the absence of a more detailed understanding of tumour immunity. The type I interferons are a family of cytokines that have long been understood to enhance the immune response to cancers, though their clinical application has led to underwhelming results in numerous types of cancer. This thesis provides new evidence that proposes the re-visitation of cancer immunotherapies that stimulate the type I interferon pathway. We show that host-derived type interferon is critical for the suppression of breast cancer metastasis through natural- killer cell activation. Induction of a type I IFN response by administering agents that mimic a viral infection (poly(I:C), a double-stranded RNA analog) proved to be powerful anti-metastatic agents in multiple pre-clinical models of triple-negative breast cancer (TNBC). This was linked to widespread immune activation which conferred NK cells with enhanced cytotoxic function to eliminate disseminated tumour cells. The efficacy of this novel immunotherapeutic approach was also found to rely upon the treatment setting in which it was used. Evidence is presented that demonstrates administration prior to primary tumour removal (neo-adjuvant therapy) as the only effective therapeutic regimen. We propose that such immunotherapies are most effective at eliminating circulating and early disseminated cells rather than established metastatic lesions. This provides some explanation to the inefficacy of previous interferon trials that were conducted in patients with late-stage metastatic disease. It also calls into question whether other immunotherapies could be used earlier in cancer treatment to maximise the chances of a clinical response. Finally, we uncover that expression of IRF9, a key transcription factor in the type-I interferon signaling pathway, accurately predicts TNBC patient prognosis. Loss of IRF9 in a patient’s primary tumour predicted significantly poorer overall survival due to metastatic spread. As we show that tumour cells are not directly responsible for the poly(I:C)-induced interferon response, we propose that patients with IRF9-negative TNBC could benefit from neo-adjuvant interferon-based immunotherapy.