DISSECTING THE TRANSFORMATION PROCESS IN MAMMARY STEM CELLS

Stem Cells (SCs) may play a critical role in cancer development, yet the direct demonstration is still lacking. The characterization of mechanisms that sustain and regulate Cancer Stem Cells (CSCs) may help elucidating their role in tumors. Using a MMTV-ErbB2 breast cancer mouse-model, we had previously shown that CSCs, through multiple rounds of symmetric divisions and extended self-renewal, drive tumor growth and the expansion of the CSC pool. Critical for this property is the lack of functional p53, that drives CSCs to symmetric divisions. Here we show that symmetric divisions and extended self-renewal in CSCs are due to the activation of c-myc as direct consequence of the loss of functional p53. In particular, c-myc is upregulated in transformed and p53-/- immortalized SCs, and enforced expression of c-myc in normal mammary SCs induces symmetric divisions and extended self-renewal, but does not transform. We show that mammary progenitors expressing c-myc acquire in vitro self-renewal properties (mammosphere formation and expansion) and in vivo regenerative potential (formation of normal mammary gland upon transplantation). Our data suggest that c-myc is critical for the maintenance of CSCs in ErbB2-mammary tumors and their aberrant self-renewing properties. This is achieved through its binary effect on CSCs (induction of symmetric divisions) and progenitors (reprogramming into CSCs). Recent studies demonstrate that c-myc over-expression in epithelial tissues induces an abnormal transcriptional pattern, similar to that of embryonic SCs, and that the same is activated in epithelial cancers and CSCs. This suggests that c-myc may be a general regulator of CSCs and their altered self-renewing properties.