(i)- Using a number of publically available data sets, we performed high-throughput analyses on primary tumors and showed that a high lysyl oxidase (LOX) expression in primary tumors from colorectal cancer patients was associated with poor clinical outcome and that LOX was expressed by tumor cells in the bone marrow from colorectal patients with bone metastasis. Indeed, we have shown that LOX is a strong determinant of tumor cell colonization in bone: it promotes survival of tumor cells in the bone marrow and impairs bone homeostasis, leading to the formation of osteolytic lesions.
We have also shown that estrogen related receptor alpha (ERRα) expression is higher in castration-resistant prostate cancer patients with bone metastases than without, and that ERRα in prostate cancer alters molecular signaling in the stroma via the regulation of periostin and TGF expression in bone metastases and in primary tumor.
Finally, we have provided novel evidence that miR-30 family members (miR-30a, miR-30b, miR-30c, miR-30d and miR-30e) act as bone metastasis suppressor genes in breast cancer, inhibiting tumor cell invasion, osteomimicry and bone destruction. We identified a number of genes associated with osteoclastogenesis stimulation (IL-8, IL-11), osteoblastogenesis inhibition (DKK-1), tumor cell osteomimicry (RUNX2, CDH11) and invasiveness (CTGF, ITGA5, ITGB3) that were direct and/or indirect targets for repression by miR-30s. Among these genes, integrin ITGA5 was a previously unknown miR-30 target. By silencing ITGA5 in breast cancer cells, colonization of the bone marrow by tumor cells was drastically reduced in vivo. Overall, our data indicate that miR-30s employ multiple mechanisms to impede breast cancer bone metastasis. These findings may pave the way to a new field of therapeutic interventions in breast cancer patients with bone metastasis.
