microRNAs, Gap Junctional Intercellular Communication and Mesenchymal Stem Cells in Breast Cancer Metastasis.

The failed outcome of autologous bone marrow transplantation for breast cancer opens the field for investigations. This is particularly important because the bone marrow could be a major source of cancer cells during tertiary metastasis. This review discusses subsets of breast cancer cells, including those that enter the bone marrow at an early period of disease development, perhaps prior to clinical detection. This population of cells evades chemotherapeutic damage even at high doses. An understanding of this population might be crucial for the success of bone marrow transplants for metastatic breast cancer and for the eradication of cancer cells in bone marrow. In vivo and in vitro studies have demonstrated gap junctional intercellular communication (GJIC) between bone marrow stroma and breast cancer cells. This review discusses GJIC in cancer metastasis, facilitating roles of mesenchymal stem cells (MSCs). In addition, the review addresses potential roles for miRNAs, including those already linked to cancer biology. The literature on MSCs is growing and their links to metastasis are beginning to be significant leads for the development of new drug targets for breast cancer. In summary, this review discusses interactions among GJIC, miRNAs and MSCs as future consideration for the development of cancer therapies.

Gap junction-mediated import of microRNA from bone marrow stromal cells can elicit cell cycle quiescence in breast cancer cells.

Bone marrow (BM) metastasis of breast cancer (BC) can recur even decades after initial diagnosis and treatment, implying the long-term survival of disseminated cancer cells in a dormant state. Here we investigated the role of microRNAs (miRNA) transmitted from BM stroma to BC cells via gap junctions and exosomes in tumor cell quiescence. MDA-MB-231 and T47D BC cells arrest in G(0) phase of the cell cycle when cocultured with BM stroma. Analyses of miRNA expression profiles identified numerous miRNAs implicated in cell proliferation including miR-127, -197, -222, and -223 targeting CXCL12. Subsequently, we showed that these CXCL12-specific miRNAs are transported from BM stroma to BC cells via gap junctions, leading to reduced CXCL12 levels and decreased proliferation. Stroma-derived exosomes containing miRNAs also contributed to BC cell quiescence, although to a lesser degree than miRNAs transmitted via gap junctions. This study shows that the transfer of miRNAs from BM stroma to BC cells might play a role in the dormancy of BM metastases.