Prognostic significance of colony-stimulating factor receptor expression in ipsilateral breast cancer recurrence

Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut 06520-8040, USA.
Clinical Cancer Research (Impact Factor: 8.72). 09/1998; 4(8):1851-6.
Source: PubMed


The macrophage colony-stimulating factor receptor (CSF-1R), the product of the c-fms proto-oncogene, regulates normal proliferation and differentiation of macrophages and trophoblasts. Recent research found abnormal expression of CSF-1R in human carcinomas of the breast, endometrium, and ovary. Furthermore, activation of CSF-1R by its ligand has been shown to regulate invasiveness and anchorage-independent growth in breast carcinoma cells. To study the significance of CSF-1R expression in breast cancer, we designed a case-controlled immunohistochemical study. We chose 80 patients from a database of 1200 early stage I or II breast cancer patients treated with conservative surgery and radiation therapy. Expression of CSF-1R in the tumors of 40 patients who experienced an ipsilateral breast tumor recurrence (IBTR) as a primary site of relapse were compared with 40 patients who had not experienced an IBTR. The index and control patients were matched by age, clinical stage, nodal status, and follow-up. Paraffin-embedded sections were immunostained with antibodies directed toward CSF-1R. For the CSF-1R antibody, a total of 28 index cases (70%) demonstrated strong staining, whereas only 16 control cases (40%) demonstrated high immunoreactivity (P = 0.007). The CSF-1R antibody showed a positive correlation for local relapse, but no correlation was found between CSF-1R expression and distant metastasis. In summary, our findings provide evidence for the poor prognostic role of CSF-1R in IBTR.

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Available from: Andrew A Gumbs, Jun 29, 2015
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    • "The proto-oncogene c-fms encodes the only known receptor (CSF-1R) for CSF-1 (Sherr and others 1985; Dai and others 2002). The expression of CSF-1 and its receptor in neoplastic epithelial breast cancer cells correlates well with a poor prognosis and is predictive of ipsilateral recurrence (Scholl and others 1994; Maher and others 1998; Kluger and others 2004). CSF-1 promotes metastasis, stimulates angiogenesis, and participates in a paracrine loop with EGF to spur tumor cell invasion in mouse models (Lin and others 2001; Aharinejad and others 2002; Aharinejad and others 2004; Wyckoff and others 2004). "
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    • "Both CSF1 and its receptor CSF1R also play roles in trophoblast survival and reproductive development (for review see [33]). Additionally, in some cancers, such as breast, ovarian and endometrial cancer, these proteins are overexpressed, and their expression can be a marker for poor prognosis [30], [32], [39], [40]. In human breast cancer, the levels of CSF1R correlate with local relapse after radiation therapy, but do not correlate with metastasis; these data were the first to suggest that high levels of CSF1R might promote radio-resistance [39]. "
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    ABSTRACT: The p53 tumor suppressor gene has a common polymorphism at codon 72 that alters its function. We previously reported that the proline 72 polymorphic variant of p53 (P72) demonstrates increased ability to transactivate a subset of genes, relative to arginine 72 (R72); one of these genes is macrophage colony stimulating factor (CSF1). At present, the mechanism(s) underlying the increased transcriptional activity of P72 toward genes like CSF1 have not been completely elucidated. Additionally, the consequences of increased transcription of genes like CSF1 by the P72 variant to the downstream p53 pathway are unknown. In this report, we address these issues. We show that the CSF1 gene contains a conserved binding site for p53, and interestingly that the P72 variant shows increased ability to bind to this site. Moreover, we show that increased CSF1/CSF1R signaling in P72 cells feeds back on the p53 pathway to enhance p53 phosphorylation, levels, and transactivation of target genes, particularly the cyclin-dependent kinase inhibitor p21 (CDKN1A). This leads to an increase in p53-mediated growth arrest, along with a concomitant decrease in apoptosis. Notably, the CSF1/CSF1R signaling axis is overexpressed in several epithelial cancers, and there is clinical evidence that this pathway plays a role in radio-resistance of some cancers. We show that cells expressing CSF1 and CSF1R are indeed radio-resistant, and further, that this effect requires p53. These combined data are the first to implicate the CSF1/CSF1R pathway in the decision between p53-mediated growth arrest and apoptosis. They are also the first to highlight a cytokine as influential in cell fate determined by p53 in epithelial cells. Finally, these data may explain the association of the P72 variant and the CSF1/CSF1R pathway with increased senescence and radio-resistance in some epithelial tumor types.
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    • "paracrine activation). Consistent with this, in breast cancer patients, the expression of both CSF-1 and its receptor in neoplastic epithelial cells strongly correlates with poor prognosis and is predictive of ipsilateral recurrence [18]–[20]. In addition, the presence of tumor associated macrophages in breast tumors also correlates with poor prognosis [19], [21] and, in mouse models, CSF-1 promotes metastasis [22], stimulates angiogenesis [23], [24] and is involved in a paracrine loop with EGF to promote tumor cell invasion [25]. "
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