Identification of Pro-Differentiation p53 Target Genes and Evaluation of Expression in Normal and Malignant Mammary Gland; Annual rept

摘要

Delta-N-p63 plays a critical role in making decision to preserve or forfeit mammary stem cells/progenitor cells self-renewal capacity. In embryonic stem cells, some transcription factors including oct3/4, nanog, c-myc and Klf-4 are critical to maintain self-renewal and multi-potential stasis. Our study revealed that these key transcription factors also exist in adult mammary stem cells/progenitor cells as well as breast cell lines such as IMEC, MCF-10A, SUM102 and MCF- 7 cells. Over-expression of ectopic delta-N-p63 could inhibit the proliferation rate of treated cells, and had diverse regulation effects on transcript level of oct3/4, nanog, c-myc and Klf-4 in infected breast cell lines. Retinoic acid treatment also could slow down the growth of treated beast cells, and change the transcript level of these self-renewal related genes. Both of RA treatment and over-expression of delta-N-p63 could increase mammosphere formation capacities in most breast cell lines including IMEC, SUM102 and MCF-7 cells. The mRNA level of oct3/4 and nanog was detectable in mouse mammary stem cells or progenitor cells enriched subpopulation. Additionally, both oct3/4 and nanog transcript level could be regulated by over- expression or removal of delta- N-p63 in mammary stem cells or progenitors fractions, respectively. In human breast cell lines such as SUM102 cells, over- expression of mouse oct3/4 and nanog could increase the mammosphere numbers significantly. On the other hand, removal of delta-N-p63 in MCF-10A cells could decrease the mammosphere formation capacity dramatically. Taken together, all these findings strongly suggested there might be correlation between delta-N- p63 and ES programming genes including oct3/4, nanog, c-myc and Klf-4 to regulate stem cell self-renewal and sustaining of pluripotency in adult mammary gland.