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The aim of this report is to review the role of CSF-1 and its receptor in neoplasms of the breast and female reproductive tract. Expression and function of CSF-1 and its receptor were studied in tumours of the human breast, ovary and endometrium. CSF-1 and its receptor, initially implicated as essential to normal monocyte development and trophoblastic implantation, have been more recently shown to be expressed by carcinomas of the breast, ovary and endometrium where activation of the receptor by ligand produced either by the tumour cells or by stromal elements stimulates tumour cell invasion by a urokinase-dependent mechanism. Breast carcinomas express wild-type CSF-1 receptors at levels comparable to those observed in trophoblast and monocytes. Ovarian and endometrial carcinomas express significantly lower levels of wild-type, functional CSF-1Rs while ovarian carcinomas also express unusual transcripts which diverge from the wild-type CSF-1R transcript in their 5' extracellular and other sequences. Tumour cell expression of CSF-1R is under the control of several steroid hormones (glucocorticoids and progestins) and tumour cell CSF-1 expression appears to be regulated by other hormones, some of which are involved in normal lactogenic differentiation. In addition, tumour cells often produce CSF-1 at such high levels that CSF-1 spills into the extracellular fluid and circulation. Measurements of circulating levels of CSF-1 have proved useful in patients with ovarian, endometrial and breast carcinoma patients both for disease detection and monitoring of response to breast carcinoma patients both for disease detection and monitoring of response to therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Colony-stimulating factor-1 receptor (CSF-1R

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.

Mammary involution is associated with degeneration of the alveolar structure and programmed cell death of mammary epithelial cells. In this study, we evaluated the expression of Fas and Fas ligand (FasL) in the mammary gland tissue and their possible role in the induction of apoptosis of mammary cells. FasL-positive cells were observed in normal mammary epithelium from pregnant and lactating mice, but not in nonpregnant/virgin mouse mammary tissue. Fas expression was observed in epithelial and stromal cells in nonpregnant mice but was absent during pregnancy. At day 1 after weaning, high levels of both Fas and FasL proteins and caspase 3 were observed and coincided with the appearance of apoptotic cells in ducts and glands. During the same period, no apoptotic cells were found in the Fas-deficient (MRL/lpr) and FasL-deficient (C3H/gld) mice. Increase in Fas and FasL protein was demonstrated in human (MCF10A) and mouse (HC-11) mammary epithelial cells after incubation in hormone-deprived media, before apoptosis was detected. These results suggest that the Fas-FasL interaction plays an important role in the normal remodeling of mammary tissue. Furthermore, this autocrine induction of apoptosis may prevent accumulation of cells with mutations and subsequent neoplastic development. Failure of the Fas/FasL signal could contribute to tumor development.J. Clin. Invest. 106:1209-1220.Terminal differentiation of the mammary gland normally takes place only during pregnancy and lactation when there is a cycle of lobulo-alveolar and ductal division followed by a period of lactation, after which cells of the secretory mammary epithelium and ducts become committed to apoptotic cell death. Gestational and lactogenic hormones regulate this pathway of differentiation. Changes in the hormonal environment at the end of lactation trigger the apoptotic signal required for "breast remodeling" (22, 23) perhaps also through the Fas-FasL system.To test the role of the Fas/FasL system in breast remodeling we studied the expression of Fas and FasL in the mammary tissue of normal BALB/c, MRL, C3H, as well as in Fas-deficient (MRL/lpr) and FasL-deficient (C3H/gld) mice through the different stages of their lactogenic differentiation. We also evaluated the presence of apoptosis during involution in wild-type MRL and C3H mice and compared it with the natural knockout MRL/lpr and C3H/gld mice. To confirm our in vivo data we also studied caspase activation and apoptosis in normal human and mouse mammary epithelial cells. In this report we describe how Fas and FasL expression is altered during pregnancy, lactation, and postlactational period, and show how these changes are hormonally regulated. We also demonstrated the role of the Fas/FasL system as a mediator of apoptosis of mammary epithelial cells during the first stage of mammary gland involution. MethodsCells and culture condition. Cells were cultured in DMEM/F-12 media containing antibiotics and antimycotics (1% vol/vol) and proper serum at 37°C in a humidified chamber (5% CO 2 in air). C...

The expression and function of CSF‐1 and its receptor were studied in tumors of the human breast, ovary, and endometrium. CSF‐1 and its receptor, initially implicated as essential to normal monocyte development and trophoblastic implantation, have been more recently shown to be expressed by carcinomas of the breast and other epithelia of the female reproductive tract where activation of the receptor by ligand produced either by the tumor cells or by stromal elements stimulates tumor cell invasion by a urokinase‐dependent mechanism. Breast carcinomas express wild‐type CSF‐1 receptors (CSF‐1R) at levels comparable to those observed in trophoblast and monocytes. Ovarian and endometrial carcinomas express significantly lower levels of wild‐type, functional CSF‐1Rs, while ovarian carcinomas also express unusual transcripts that diverge from the wild‐type CSF‐1R transcript in their 5′ extracellular domain sequences. Tumor cell expression of CSF‐1R is under the control of several steroid hormones (glucocorticoids and progestins) and the binding of several bHLH transcription factors, while tumor cell expresion of CSF‐1 appears to be regulated by other hormones, some of which are involved in normal lactogenic differentiation. In addition, tumor cells often produce CSF‐1 at such high levels that the cytokine spills into the extracellular fluid and circulation. Measurements of circulating levels of CSF‐1 have proved useful in patients with ovarian, endometrial, and breast carcinoma both for disease detection and monitoring of response to therapy. CSF‐1 and its receptor appear to be an important receptor/ligand pair in the biology of breast cancers and tumors of the female reproductive tract where they may regulate functions similar to those they control during macrophage activation and placental implantation. Mol Reprod Dev 46:71–74, 1997. © 1997 Wiley‐Liss, Inc.

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