The COMMA-Dβ-geo cell line has been shown to contain a permanent subpopulation of progenitor cells that are enriched in outgrowth potential. Using the COMMA-Dβ-geo cell line as a model, we sought to study the radioresistance of mammary progenitor cells. Using the putative progenitor cell marker stem cell antigen 1 (Sca1), we were able to isolate a discrete subpopulation of Sca1⁺ multipotent cells from the immortalized COMMA-Dβ-geo murine mammary cell line. At a clinically relevant dose, the Sca1⁺ cells were resistant to radiation (2 Gy). Sca1⁺ cells contained fewer γ-H2AX⁺ DNA damage foci following irradiation, displayed higher levels of endogenous β-catenin, and selectively upregulated survivin after radiation. Expression of active β-catenin enhanced self-renewal preferentially in the Sca1⁺ cells, whereas suppressing β-catenin with a dominant negative, β-engrailed, decreased self-renewal of the Sca1⁺ cells. Understanding the radioresistance of progenitor cells may be an important factor in improving the treatment of cancer. The COMMA-Dβ-geo cell line may provide a useful model to study the signaling pathways that control mammary progenitor cell regulation.