Purpose: Macrophage colony-stimulating factor-1 receptor (CSF-1R) is a transmembrane tyrosine kinase receptor, which is abnormally expressed in invasive breast cancer. Small cohort studies have demonstrated that increased expression of CSF-1R is associated with ipsilateral breast cancer recurrence. Correlation with survival has not been reported. Our aim was to further evaluate the role of CSF-1R in breast cancer, by studying the expression of CSF-1R in a large cohort of clinical specimens.Experimental Design: Tissue microarrays containing 301 node-negative and 280 node-positive cases were used. Immunohistochemical staining was performed and correlated with overall survival, nodal status, and other clinicopathological data.Results: CSF-1R expression was strongly associated with nodal status. Of the node-negative cases, 114 (38.9%) stained positive for CSF-1R, whereas 189 (67.5%) of the node-positive cases expressed CSF-1R (P < 0.0001). CSF-1R expression is also associated with larger tumor size (P ‫؍‬ 0.02). Positive staining was strongly associated with decreased survival (P ‫؍‬ 0.0003). Among node-negative patients, CSF-1R expression was associated with decreased overall survival (P ‫؍‬ 0.045), whereas among node-positive patients, it was not (P ‫؍‬ 0.47). In multivariate analysis, CSF-1R was not independent of nodal status as a predictor of survival.Conclusions: CSF-1R expression is a strong predictor of poor outcome in nonmetastatic breast cancer. It is significantly more frequently expressed in patients with nodal involvement. Among the node-negative patients, it has a stronger association with survival than among the nodepositive patients. Our findings support other preclinical findings that CSF-1R may be involved in local invasion and metastasis. Thus, this receptor may be an effective target for therapeutic agents.

The fms oncogene encodes the macrophage colony-stimulating factor receptor (CSF1R), a transmembrane tyrosine kinase receptor, which is abnormally expressed in breast cancer. Transfection of wild-type CSF1R into HC11 mammary epithelial cells (HC11-CSF1R) renders the transfectants capable of in vitro local invasion and in vivo tumorigenesis. Transfection with CSF1R mutated to express phe at the tyr-721 autophosphorylation site (HC11-CSF1R-721) creates a phenotype that lacks metastastic competence but maintains local invasiveness. Conversely, HC11 cells transfected with CSF1R mutated at tyr-807 (HC11-CSF1R-807) retain their metastatic competence, but are not locally invasive. Our aims were to determine which genes were differentially expressed with transfection of HC11 with wild-type CSF1R, and to determine the effect of mutation at the autophosphorylation sites on gene expression, using 4.6 K cDNA microarrays. Complementary DNA from HC11, HC11-CSF1R-721 and HC11-CSF1R-807 were each hybridized together with HC11-CSF1R on individual arrays. A principal component spectral method combined with prenormalization procedures was used for sample clustering. Differentially expressed genes were identified by the analysis of variance. Confirmation by Northern blotting was performed for MAP kinase phosphatase-1, WDNM1 (extracellular proteinase inhibitor), Trop 2 (tumor-associated calcium signal transducer-2), procollagen type IV alpha, secretory leukoprotease inhibitor, prenylated snare protein Ykt6, ceruloplasmin and chaperonin 10. Many of these genes have not previously been associated with tumor invasion and metastasis. We have successfully identified genes that can be linked to the invasive phenotypes or to tumorigenesis. These genes provide a basis for further studies of metastatic progression and local invasiveness, and can be evaluated as therapeutic targets. The cfms proto-oncogene encodes the only known receptor for the macrophage colony-stimulating factor (CSF1). CSF1R is a transmembrane tyrosine kinase receptor, and its ligand, CSF1, has soluble, membrane-bound and cell matrix-associated isoforms. 1-3 The CSF1R/CSF1 receptor/ligand pair has essential physiologic functions in monocyte and macrophage differentiation, 4,5 embryonic implantation and placental development, and lactogenic differentiation of the human breast. 6-8 Abnormally high CSF1R expression has clinically been associated with aggressive breast, ovarian, endometrial, and prostate cancer. [9][10][11][12][13][14][15][16] Most invasive breast carcinoma cells express readily detectable levels of activated CSF1R. 13 Studies 17 have shown that invasive breast cancer cells coexpress the ligand CSF 1, but adjacent in situ carcinoma cells do not. Moreover, in early-stage breast cancer patients treated with local therapy only, high levels of CSF1R expression also have been associated with a higher likelihood of ipsilateral recurrence. 18 To further evaluate the role of CSF1R in invasion and metastasis, we studied a mouse cell line model 19 that utilized the HC11...

The observed increases in the expression of CSF-1 and its receptor during lactogenesis and the regulation of CSF-1/CSF-1R by lactogenic hormones suggests that this cytokine/receptor pair might play a regulatory role in the cellular events leading to the lactogenic differentiation of mammary epithelial cells.

Quantifiable markers of apoptosis such as caspase-3 activation have the potential to predict the clinical response to chemotherapy. Application of this assay in clinical laboratories could optimize the potential for efficient treatment and avoid the toxicities of ineffective drugs.

SummaryThe prognostic significance of SOCS3 protein expression was determined in de novo follicular lymphomas (FL) with t(14;18) and bcl-2 overexpression. Presentation lymph nodes from 82 FL patients for whom clinical information was available were immunohistochemically segregated into SOCS3-positive (n ¼ 42) or -negative (n ¼ 40) cohorts, and overall survival (OS) was analysed. SOCS3-positive FL patients had a median OS of 10 years compared with 22 years in SOCS3-negative patients (P ¼ 0AE001, log rank test). After adjusting for Follicular Lymphoma International Prognostic Index subgroups, SOCS3 overexpression remained an independent predictor of decreased OS (P < 0AE001). These findings suggest that overexpression of SOCS3 may be an independent poor prognostic variable in patients with de novo FL.