Normal and neoplastic non-stem cells can spontaneously convert to a stem-like state. This study shows that differentiated human mammary epithelial cells can dedifferentiate into stem-like cells, and oncogenic transformation enhances this process, allowing non-stem cancer cells to generate cancer stem cell (CSC)-like cells in vitro and in vivo. The differentiation state of normal cells-of-origin significantly influences post-transformation behavior. These findings suggest that normal and CSC-like cells can arise de novo from more differentiated cell types, and that hierarchical models of mammary stem cell biology should include bidirectional interconversions between stem and non-stem compartments. The observed plasticity may allow derivation of patient-specific adult stem cells without genetic manipulation and has important implications for therapeutic strategies to eradicate cancer. The study also demonstrates that transformed epithelial cells can spontaneously generate CSC-like cells in vivo, highlighting the role of the tumor microenvironment in this process. The results indicate that the biological state of normal cells-of-origin before transformation strongly influences the behavior of their descendants following transformation. The findings support the idea that the biological state of cells-of-origin is an important determinant of the phenotype of their transformed derivatives. The study provides evidence that oncogenic transformation of mammary stem-like cells yields more aggressive tumors than oncogenic transformation of differentiated mammary epithelial cells. The results emphasize the pathological implications of cellular plasticity in cancer development, progression, and recurrence. Further research is needed to determine the mechanism underlying the de novo generation of CSCs from non-CSCs in vivo, with the promise of potential novel targets for future cancer therapies aimed at eradicating CSCs.Normal and neoplastic non-stem cells can spontaneously convert to a stem-like state. This study shows that differentiated human mammary epithelial cells can dedifferentiate into stem-like cells, and oncogenic transformation enhances this process, allowing non-stem cancer cells to generate cancer stem cell (CSC)-like cells in vitro and in vivo. The differentiation state of normal cells-of-origin significantly influences post-transformation behavior. These findings suggest that normal and CSC-like cells can arise de novo from more differentiated cell types, and that hierarchical models of mammary stem cell biology should include bidirectional interconversions between stem and non-stem compartments. The observed plasticity may allow derivation of patient-specific adult stem cells without genetic manipulation and has important implications for therapeutic strategies to eradicate cancer. The study also demonstrates that transformed epithelial cells can spontaneously generate CSC-like cells in vivo, highlighting the role of the tumor microenvironment in this process. The results indicate that the biological state of normal cells-of-origin before transformation strongly influences the behavior of their descendants following transformation. The findings support the idea that the biological state of cells-of-origin is an important determinant of the phenotype of their transformed derivatives. The study provides evidence that oncogenic transformation of mammary stem-like cells yields more aggressive tumors than oncogenic transformation of differentiated mammary epithelial cells. The results emphasize the pathological implications of cellular plasticity in cancer development, progression, and recurrence. Further research is needed to determine the mechanism underlying the de novo generation of CSCs from non-CSCs in vivo, with the promise of potential novel targets for future cancer therapies aimed at eradicating CSCs.