The novel lupus antigen protein Acheron promotes breast cancer progression

4141 Gene microarray databases have shown that the newly described La protein family member Acheron (Achn) is up-regulated in basal-like breast cancers relative to normal mammary tissue. We sought to determine if Achn expression could exacerbate the malignant properties of breast cancer cells in human. Retroviral constructs were created that encoded wild-type Achn (AchnWT), as well as Achn lacking either its nuclear localization signal (AchnNLS) or its nuclear export signal (AchnNES), fused in frame with enhanced GFP. These constructs were subsequently introduced into a breast cancer line, MDA-MB-231, through retroviral infection. Both AchnWT and AchnNES enhanced cell proliferation and the invasive activity of the engineered cells relative to controls, while ectopic AchnNLS did not have ability to alter these activities. Consistent with the increased invasive behavior, cells expressing either AchnWT or AchnNES expressed elevated levels of active MMP-9 and VEGF. Using an MMP-9 promoter-luciferase reporter system, we found that both AchnWT and AchnNES but not AchnNLS were able to drive luciferase expression, suggesting that nuclear Achn plays a role in MMP-9 transcription. Achn-engineered MDA-MB-231 cells were then injected into 4-week old SCID/Beige mice and the resulting tumors examined over a 7 week period. AchnWT and AchnNES expressing tumors were five-fold larger than those generated from control or AchnNLS expressing cells. Concomitantly, an immunohistological analysis displayed an approximately five-fold increase in expression levels of VEGF in both the AchnWT and AchnNES expressing tumors relative to that seen in the control or AchnNLS tumors. Taken together, these data suggest that nuclear Achn can enhance the metastatic behavior of breast cancer cells in part by altering proliferation, invasion, and angiogenesis at several levels.