The effect of heme oxygenase-1 on breast cancer metastasis in vitro and in vivo

• Main Author: Kim, Ada Yongyeon
• Language: English
• Published: University of British Columbia 2014
• Online Access: http://hdl.handle.net/2429/46673

The metastatic spread of cancer is linked to over 90% of cancer-related deaths. Therapies designed to prevent the dissemination of metastatic cells from the primary tumour is a therapeutic strategy to improve outcome for patients at risk of developing metastatic disease. Heme oxygenase-1 (HMOX1) is the rate-limiting enzyme in heme catabolism and is induced by various stress stimuli. The role of HMOX1 in breast cancer metastasis is conflicting with some groups indicating that HMOX1 promotes metastasis while others indicating that HMOX1 reduces metastatic spread. Previously in our laboratory, HMOX1 expression was chemically induced with hemin, a potent and effective HMOX1 inducer, in murine mammary carcinoma cells to determine the effect of HMOX1 on tumour cell migration and invasion. Hemin reduced migration and invasion of all three cell lines when assessed by Boyden chamber transwell assays. Therefore, we hypothesize that HMOX1 reduces breast cancer metastasis by decreasing tumour cell migration and invasion. We used three different murine mammary carcinoma cell lines as models for breast cancer: 67NR – noninvasive/nonmetastatic, 4TO7 – invasive/metastatic, 4T1 - highly aggressive metastatic behavior. We increased HMOX1 expression genetically or by chemical induction with another HMOX1 inducer, cobalt protoporphyrin (CoPP), to determine the effect of HMOX1 on migration and invasion. CoPP and HMOX1 overexpression reduced migration of all tumour cells in vitro. Interestingly, HMOX1 overexpression decreased invasion of 4T1 cells, but increased the invasion of 67NR and 4TO7 cells, modeling the dichotomy of HMOX1’s influence on breast cancer cell invasion. We also assessed the effect of HMOX1 overexpression and knockdown on lung metastases in vivo. In 4T1 tumours, HMOX1 overexpression had no effect on primary tumour growth or lung metastases. On the other hand, in 4T1 tumours with HMOX1 knockdown, there was a reduction in tumour growth and in lung metastases.