IDENTIFICATION IN BREAST CANCER CELLS OF A NOVEL MECHANISM OF CSF-1R SIGNALING WHICH INVOLVES ITS NUCLEAR TRANSLOCATION AND BINDING TO THE PROMOTER OF GENES RELEVANT TO CANCER PROGRESSION

The Colony-Stimulating Factor 1 (CSF-1) and its receptor CSF-1R physiologically regulate the monocyte/macrophage system, trophoblast implantation and breast development. An abnormal expression of CSF-1R, associated or not whit that of CSF-1, has been also documented in several human epithelial tumors, including breast carcinomas. We recently showed that CSF-1/CSF-1R pair sustains the proliferation of breast cancer cell lines via an autocrine loop which involves ERK1/2 activation. CSF-1R localized in the nucleus and nucleolus of breast cancer cells, both in cell lines and tissue samples, irrespectively of intrinsic molecular subtypes of breast cancer. By chromatin immunoprecipitation we found that CSF-1R binds to the promoters of genes involved in cell proliferation, DNA-repair and other cellular functions relevant to cancer progression. Accordingly, the expression of many of these genes was changed following CSF-1R silencing. These results sustain CSF-1/CSF-1R targeting in breast cancer and identified a new mechanism of CSF-1R signaling which involves its nuclear localization.