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Expression of CSF-I and CSF-I Receptor by Normal Lactating Mammary Epithelial Cells

Department of Therapaeutic Radiology, HRT256, Yale University School of Medicine, P.O. Box 208040, New Haven, CT 06520-8040. eva.sapi{at}yale.edu

Maryann B. Flick, PhD

Sofya Rodoy

Daryl Carter, MD

Barry M. Kacinski, MD, PhD

Department of Therapeutic Radiology, Obsterics and Gynecology, and Dermatology and Pathology, Yale University School of Medicine, New Haven, Connecticut

Objective: Previous studies suggested a potential role for macrophage colony stimulating factor (CSF-1) in lactogenic differentiation of the breast. The aim of this study was to define the regulation of CSF-1 and its receptor (CSF-1R, the product of c-fms proto-oncogene) by lactogenic hormones in the breast in vivo during pregnancy and lactation and in vitro in organ culture and mammary epithelial cell lines.

Methods: Immunohistochemical staining assays for the expression of CSF-1 and CSF-1R antigens were performjed on sections of breast biopsies from nonpregnant (n = 10), prepartum (n = 4), and postpartum lactating patients (n = 7_) and on sections of human mammary glands culture in the presence of the lctogenic hormones insulin, prolactin, and glucocorticoids. Northern blot analyses were used to study the regulation of CSF-1 and CSF-1R by these same lactogenic hormones in normal and neoplastic mammary epithelial cell lines in cell culture.

Results: Normal, nonlactating mammary epithelium did not express CSF-1R and synthesized only low levels of CSF-1. During lactation, significant levels of both proteins could be observed in the epithelial cells that line actively lactating ducts and alveoli. Very similar increases in epithelial cell expression of CSF-1 and CSF-1R were observed in organ cultures of normal mammary gland biopsies exposed to prolactin, insulin, and glucocorticoids. Colony stimulating factor mRNA levels were increased by prolactin and/or insulin in a normal mammary epithelial cell line, while glucocorticoids had no apparent effect on CSF-1 mRNA levels. In contrast, we found that the levels of CSF-1R transcript are regulated primarily by glucocorticoids in breast carcinoma cells, while prolactin merely modulates the glucocorticoid effect.

Conclusion: 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.

Key Words: c-fms • lactogenesis • breast cancer • organ culture • Ru 486 • prolactin

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