SDF-1α regulation in breast cancer cells contacting bone marrow stroma is critical for normal hematopoiesis

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Abstract
Breast cancer cells (BCCs) show preference for the bone marrow (BM). An animal model showed 2 populations of BCCs in the BM with regard to their cycling states. An in vitro model of early BC entry into BM showed normal hematopoiesis. Here, we show a critical role for BCC-derived SDF-1α in hematopoietic regulation. The studies used a coculture of BM stroma and BCCs (cell lines and stage II BCCs). Northern blots and enzyme-linked immunosorbent assay (ELISA) showed gradual decreases in SDF-1α production in BCCs as they contact BM stroma, indicating partial microenvironmental effects caused by stroma on the BCCs. SDF-1 knock-down BCCs and increased exogenous SDF-1α prevented contact inhibition between BCCs and BM stroma. Contact inhibition was restored with low SDF-1α levels. Long-term culture-initiating assays with CD34+/CD38–/Lin– showed normal hematopoiesis provided that SDF-1α levels were reduced in BCCs. Gap junctions (connexin-43 [CX-43]) were formed between BCCs and BM stroma, with concomitant interaction between CD34+/CD38–/Lin– and BM stroma but not with the neighboring BCCs. In summary, SDF-1α levels are reduced in BCCs that contact BM stroma. The low levels of SDF-1α in BCCs regulate interactions between BM stroma and hematopoietic progenitors, consequently facilitating normal hematopoiesis.
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