Parathyroid hormone-related protein (PTHrP) is produced by many tumors including breast cancer. We have reported that Ets1 factor activates P3 PTHrP promoter in our model of tumorigenic breast cancer cell and not in pre- or non-tumorigenic cell lines, thus contributing to an increased PTHrP production. In this study, gel retardation assays revealed that Etsl and its promoter binding site (EBS) specifically formed complexes whose abundance correlates with Ets1 levels in the three cell lines. Coexpression of Etsl and CBP induced a synergistic activation of the P3 promoter only in the tumorigenic cell line. This synergism required the integrity of the EBS and was abrogated by E1A. All breast cancer cell lines showed high basal concentrations of phosphorylated CREB. Moreover a CRE-like sequence was also required for Ets1/CBP synergy and, finally, CREB expression was found to enhance the PTHrP P3 promoter activity. Thus a multipartite complex of transcription factors and coactivators seems to regulate PTHrP transcription and contribute to the alterations that promote tumorigenic behavior in breast epithelial cells.