CSF1 Determines CSF1R Cytoplasmic Nuclear Shuttling in Breast Cancer Cells

Background: Breast cancer is the most prevalent cancer in non-smoking women and the second leading cause of cancer-related deaths in western countries. The Colony- Stimulating Factor 1 (CSF1) and its receptor CSF1R physiologically regulate the monocyte/macrophage system, trophoblast implantation and breast development. An abnormal expression of CSF1R, associated or not witht that of CSF1, has been also documented in several human epithelial tumors, including breast carcinomas. Despite the fact that the expression of both CSF1 and CSF1R strongly correlates with poor prognosis of breast cancer, scanty data have been obtained on CSF1R signaling in neoplastic cells. Methods: Breast cancer cell lines or tissue samples of different molecular classes (i.e. presence/absence of estrogen or progesterone receptors or HER2 over-expression) were used to study the intracellular localization of CSF1/CSF1R by confocal microscopy, cell fractionation or immuno-histochemistry. Results: We found that CSF1R is localized in the nucleus and nucleolus of breast cancer cells, both in cell lines and tissue samples and irrespectively of the molecular class of breast cancer, and that this localization depends on CSF-1. Moreover, we found by chromatin immunoprecipitation assay that CSF1R binds the promoters of cyclin D, c-myc and c-Jun, genes known to be regulated by CSF1/CSF1R and relevant for CSF1-induced cell proliferation. Conclusions: The identification of a new mechanism of response to CSF1 in breast cancer cells points to the relevance of CSF1R in breast cancer development and treatment.