Lysyl Oxidase Interacts with Hormone Placental Lactogen and Synergistically Promotes Breast Epithelial Cell Proliferation and Migration

Abstract

Lysyl oxidase (LOX), an extracellular amine oxidase, catalyzes the cross-linking of collagen and elastin. LOX has been also shown to play an essential role in promoting the invasive and metastatic potential of breast tumor cells. However, the LOXinteracting factors in these processes are not known. In this study, we identified placental lactogen (PL), a member of the growth hormone/prolactin hormone family, as a LOX-interacting partner using yeast two-hybrid screens. PL is normally only expressed in placental syncytiotrophoblasts, but PL genes are amplified and expressed in a high percentage of invasive ductal breast carcinomas. We confirmed LOX-PL interactions using far Western and solid phase binding assays. In activity assays, PL was not a substrate or inhibitor of LOX. We further demonstrated that PL is expressed in breast tumor epithelial cells and detected LOX-PL interactions by coimmunoprecipitation in invasive breast cancer cells. In MCF-10A normal breast epithelial cells stably expressing LOX, PL, or both, LOX had no effect on cell proliferation, PL alone increased proliferation by 49%, and coexpression of LOX and PL led to a 121% increase in cell proliferation. Unlike in tumor cells, LOX did not induce a more migratory phenotype in MCF-10A cells; nor did PL. However, their coexpression resulted in a 240% increase in cell migration, suggesting that these interactions may be highly relevant to the transition of epithelial cells toward a migratory phenotype during the development and progression of breast carcinoma and a significant role for LOX-PL interactions in epithelial cell behavior.

Unexploited therapies in breast and prostate cancer: blockade of the prolactin receptor

“…A retrospective study of 233 patients with invasive breast carcinomas found that 31% and 25% of invasive ductal and lobular carcinomas, respectively, stained positively for hPL [45], while non-neoplastic breast epithelium was negative for this antigen. More recently, hPL was detected by Western blotting in several breast cancer cell lines [46]. Whereas we did not find previous reports on hPL expression in the human prostate, this issue warrants further investigation.…”

Association of Expression Aberrances and Genetic Polymorphisms of Lysyl Oxidase with Areca-Associated Oral Tumorigenesis

“…A recent study has specified that LOX was not sufficient to induce migration of normal breast epithelial cells. However, the interaction between LOX and placenta lactogen can synergistically promote breast epithelial migration (20). Providing that oral epithelial cells may lack LOX-interacting molecules that caused the silencing of LOX-associated migration regulation, the induction of migration or invasion could be the consequence of propeptide reduction through LOX knockdown.…”

The HIF-1–Inducible Lysyl Oxidase Activates HIF-1 via the Akt Pathway in a Positive Regulation Loop and Synergizes with HIF-1 in Promoting Tumor Cell Growth

“…LOX and HIF-1a act in synergy to promote tumor cell proliferation Both HIF-1a and LOX are known to promote tumor cell growth and survival (9,32). We wanted to determine whether the mutual regulation of LOX and HIF-1a could be involved in colorectal tumor cell growth.…”

“…LOX is a copper-dependent amine oxidase that catalyzes the cross-linking of collagen and elastin in the extracellular matrix (ECM), thereby increasing insoluble matrix deposition and tensile strength (8). LOX has been shown to enhance tumor cell proliferation and invasion (5,9,10), particularly by increasing ECM stiffness (11).…”