A growing number of studies indicate the importance of the lysyl oxidase family in the promotion of epithelial neoplasms towards their more aggressive forms. However, the role of individual family members in carcinoma progression has yet to be ascertained. In this study, we analyzed LOXL2 expression in malignantly transformed MCF-7 and normal MCF-10A mammary epithelial cell line clones stably transduced with LOXL2 in vitro, and in normal and cancerous breast tissue samples in vivo. We found LOXL2 to be catalytically active in both MCF-7 and MCF-10 clones. LOXL2 overexpression promoted a more mesenchymal morphology in both cell types, but LOXL2-induced increase in migratory ability could only be established in MCF-7 clones. We demonstrated altered localization of the LOXL2 protein in breast cancer tissue compared to normal mammary tissue, and altered localization and processing of LOXL2 protein in breast cancer cell lines compared to normal cell lines, which may allow LOXL2 to interact with different intra and extracellular components during tumor progression. Results support the role of LOXL2 in selectively promoting a metastatic phenotype in breast tumor cells. Additional data suggest epigenetic molecular mechanisms in tumor specific regulation of LOXL2 expression that could be explored as a molecular target in the prevention of breast cancer progression. ' UICCKey words: LOXL2; epigenetic regulation; breast cancer Lysyl oxidase-like 2 (LOXL2) belongs to a family of 5 proteins characterized by a conserved carboxy-terminal copper-binding domain and a lysyl-tyrosyl quinone cofactor, which are necessary for the amine oxidase activity of these extracellular matrix (ECM) enzymes.1,2 Indeed, catalytic activity for LOXL2 has been confirmed in Chinese hamster ovary cells.3 This study also reported that LOXL2 activity was not inhibited by b-aminoproprionitrile (BAPN), making it different from the BAPN-sensitive catalytic activity reported for LOX, 4 LOXL, 5,6 and LOXL4, 7 despite the high homology within their catalytic region. The relationship between the catalytic activity and physiologic or pathologic function of LOXL2 has yet to be characterized.In our previous studies, we reported high levels of LOXL2 mRNA expression in highly invasive, metastatic breast cancer cell lines and highly tumorigenic, metastatic mouse squamous and spindle cell carcinomas, compared to absent expression in noninvasive, nonmetastatic breast cancer cell lines and a nontumorigenic keratinocyte cell line. 8,9 At the tissue level, we reported the association of increased LOXL2 protein expression with poorly differentiated colon adenocarcinoma and mucinous carcinoma, both of which have aggressive behavior and high incidence of metastasis.10,11 This observation is supported by a recent report of increased LOXL2 mRNA expression in colon tumors and liver metastases compared to normal colon. 12 In breast cancer, increased LOXL2 protein expression was associated with higher tumor grade, decreased overall and disease-free survival in lymphnode negat...
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