Bone is a frequent site for breast cancer metastasis. Conditioning of local tumor microenvironment through crosstalk between tumor cells and bone resident cells in the metastatic niche is a major driving force for bone colonization of cancer cells. This study demonstrates that Myocardin-related transcription factor (MRTF - a major cofactor for the transcription factor serum-response factor, SRF) activity in breast cancer cells is required for their ability to promote osteoclast differentiation of bone marrow-derived monocytes and colonize in bone. MRTF depletion in breast cancer cells affects a wide range of cell-secreted osteoclast-regulatory factors including connective tissue growth factor (CTGF), a prominent bone metastasis-associated gene that exhibit strong positive association in expression with MRTF activity in human breast cancer. Rescue experiments demonstrate that CTGF is an important paracrine mediator of pro-osteoclastogenic action of MRTF in breast cancer cells. Both SRF-dependent and -independent (SAP-domain directed) functions of MRTF are required for its ability to regulate CTGF expression and osteoclast differentiation. In conclusion, this study uncovers a novel MRTF-directed tumor-extrinsic mechanism of bone colonization of cancer cells and suggest that MRTF inhibition could be a novel strategy to suppress osteoclast activity and skeletal involvement in metastatic breast cancer.