Laminin-511: a key regulator of breast cancer metastasis
AffiliationSir Peter MacCallum Department of Oncology
Document TypePhD thesis
Access StatusOpen Access
© 2018 Dr. Selda Star
Cancer progression is invariably associated with changes in the stromal microenvironment, most notably, the extracellular matrix (ECM) composition. Laminins (LM) are a family of large trimeric ECM proteins comprised of at least 16 isoforms that differ by their α, β and γ chain combination. Their expression and function in normal development and in pathologies are temporally regulated in a tissue specific manner and dictated in part by their interactions with specific cell surface integrin receptors. Work from our laboratory indicates that the more recently discovered LM-511 (α5β1γ1 trimer, formerly LM-10) is the most relevant isoform contributing to breast cancer metastasis. Unlike LM-111 (α1β1γ1 trimer, formerly LM-1) and LM-332 (α3β3γ2 trimer, formerly LM-5), LM-511 expression is often sustained or increased in advanced tumours and metastases (Chia et al., 2007). Consistent with this work, our laboratory showed that LM-511 promotes pro-metastatic responses in vitro including cell adhesion, migration, invasion and protease (MMP-9) expression and this correlated with high expression of LM-binding integrin β4 receptor. To provide more direct evidence for the role of LM-511 and integrin β4 in breast cancer metastasis, here we have used a gene knockdown approach to suppress their expression in a syngeneic mouse model of spontaneous breast cancer metastasis. We demonstrate for the first time that suppression of tumour LM511 or its integrin α6β4 receptor significantly reduces circulating tumour cells and metastasis, particularly to bone, the major site of metastasis for breast cancer. When repeated in an experimental model of metastasis, bone metastasis was significantly reduced by the down-regulation of LMα5 or integrin β4 expression. Collectively, our results identify a role for LM-511 and integrin β4receptor in both early and late stage breast cancer metastasis. We present evidence that LM-511 and integrin β4 regulate metastasis by modulating epithelial-mesenchymal transition (EMT) and that this pathway is enhanced via MMP-9 proteolytic cleavage of LM-511. Protein analysis and immunofluorescence in vitro and immunohistochemistry in vivo demonstrated that when LMα5 or integrin β4 is down-regulated, the expression of mesenchymal markers N-cadherin, vimentin, SNAI1/2, TWIST and ZEB1/2 is reduced. Studies have reported that interactions between tumour cells and surrounding ECM can influence the acquisition of drug resistance (Senthebane et al., 2017). Herein, we show that when LM-511 or β4 is suppressed tumour cells become more sensitive to chemotherapeutic agents. Furthermore, treating cells with Lebein-1 (disintegrin) blocks LM/integrin interactions and further enhances their sensitivity to current therapies. In summary, we show that interfering with LM-511 production or integrin β4 receptor expression significantly reduces triple negative (TN) breast cancer metastasis to bone and soft tissues and enhances their sensitivity to current breast cancer therapies.
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