SOX genes encode a family of high-mobility group transcription factors that play critical roles in organogenesis. The functional specificity of different SOX proteins and the tissue specificity of a particular SOX factor are largely determined by the differential partnership of SOX transcription factors with other transcription regulators, many of which have not yet been discovered. Virtually all members of the SOX family have been found to be deregulated in a wide variety of tumors. However, little is known about the cellular and molecular behaviors involved in the oncogenic potential of SOX proteins. Using cell culture experiments, tissue analysis, molecular profiling, and animal studies, we report here that SOX2 promotes cell proliferation and tumorigenesis by facilitating the G(1)/S transition and through its transcription regulation of the CCND1 gene in breast cancer cells. In addition, we identified beta-catenin as the transcription partner for SOX2 and demonstrated that SOX2 and beta-catenin act in synergy in the transcription regulation of CCND1 in breast cancer cells. Our experiments not only determined a role for SOX2 in mammary tumorigenesis but also revealed another activity of the multifunctional protein, beta-catenin.