Stem and progenitor cells polarise and divide asymmetrically to regulate cell diversification during tissue development. Tight control of this process is essential during normal tissue morphogenesis and involves cell polarity mechanisms to segregate cell fate determinants and to reorientate the mitotic spindle appropriately. Loss of polarity is a hallmark of cancer and it has been suggested that impairment of asymmetric cell divisions could result in the inappropriate outgrowth of uncommitted cells leading to tumour formation. GPSM2 is a polarity protein which acts as a key component of the asymmetric division machinery. GPSM2 coordinates spindle orientation and segregation of cell fate determinants during asymmetric divisions of Drosophila progenitors and mutant Drosophila neuroblasts lacking GPSM2 have been shown to form tumours when transplanted into adult hosts. Whilst these Drosophila studies have supported a role for defective asymmetric cell divisions in tumour formation, further evidence in mammalian models of cancer has been lacking.
We have recently identified GPSM2 in a polarity tumour suppressor screen and shown that GPSM2 loss cooperates with activated RasV12 to allow invasion and anchorage independent growth in the human mammary epithelial cell line MCF10A. Depletion of GPSM2 also accelerated tumour growth in an orthotopic xenotransplant model of breast cancer. We have now begun to characterise a role for GPSM2 in the control of mammary stem cell and luminal cell commitment. Our findings reveal that deregulation of GPSM2 inhibits the repopulating frequency of mammary stem cells and in turn favours the ectopic expansion of CD61+ luminal progenitor cells, which have been identified as a cell of origin for estrogen receptor negative breast cancers. Indeed we find that low GPSM2 expression is associated with worse outcomes only in women with basal-like or HER2+ tumour subtypes. These studies describe a distinct role for GPSM2 in the hierarchical model of mammary gland development and demonstrate a potential role for GPSM2 in breast cancer.