PML: a tumor suppressor that regulates cell fate in mammary gland.

The tumor suppressor promyelocytic leukemia protein (PML) is possibly unique in that its tumor suppressive functions may be attributed to both the protein and the conspicuous nuclear bodies (PML-NBs) that PML builds. Untangling the role of either the protein or its domain in cell fate has been a decade long task which has just received new impetus from developmental biologists. PML appears to play a central role in regulating stem and progenitor cell fate in tissues as diverse as blood, brain and breast. Our studies have uncovered an inverse relationship between the activity of certain Stat transcription factors and PML in controlling normal mammary gland development and the regulation of lineage commitment. Genetic loss of Pml delays differentiation of the milk-producing alveolar cells and disrupts ductal development, defects which may result from a skewing of the progenitor population to favor estrogen receptor positive cells (ERalpha). This is of considerable interest as ERalpha cells are non-cycling in normal breast while promiscuous cell cycle entry is a feature of these cells in breast cancer. These data begin to show the cell types and tissues that are most sensitive to PML dose and provide new perspectives for the regulation of mammary gland development and tumorigenesis.