Members of the fatty acid binding protein family are differentiation factors for the mammary gland.

Abstract

Abstract. Mammary gland development is controlled by systemic hormones and by growth factors that might complement or mediate hormonal action. Peptides that locally signal growth cessation and stimulate differentiation of the developing epithelium have not been described. Here, we report that recombinant and wild-type forms of mammary-derived growth inhibitor (MDGI) and heart-fatty acid binding protein (FABP), which belong to the FABP family, specifically inhibit growth of normal mouse mammary epithelial cells (MEC), while growth of stromal cells is not suppressed. In mammary gland organ culture, inhibition of ductal growth is associated with the appearance of bulbous alveolar end buds and formation of fully developed lobuloalveolar structures. In parallel, MDGI stimulates its own expression and promotes milk protein synthesis. Selective inhibition of endogenous MDGI expression in MEC by antisense phosphorothioate oligonucleotides suppresses appearance of alveolar end buds and lowers the ~-casein level in organ cultures. Furthermore, MDGI suppresses the mitogenic effects of epidermal growth factor, and epidermal growth factor antagonizes the activities of MDGI. Finally, the regulatory properties of MDGI can be fully mimicked by an l 1-amino acid sequence, represented in the COOH terminus of MDGI and a subfamily of structurally related FABPs. This peptide does not bind fatty acids. To our knowledge, this is the first report about a growth inhibitor promoting mammary gland differentiation.ROWTH development, and differentiation of epithelial tissues are multistage processes that are driven by a combination of paracrine and autocrine signaling factors and interactions of a cell with its extracellular matrix (reviewed in 51, 60, 62). In the mammary gland, these complex interactions are regulated by various steroid and peptide hormones (29,32,46,60). Development of the mouse mammary gland at puberty is characterized by sparsely branching ducts which invade the stroma, followed by the development of lobuloalveolar structures and functional differentiation, i.e., synthesis of milk constituents at pregnancy (1,17,32). By use of endocrine ablation (44), organ culture systems (1,35,54,65) and mammary cells (MEC) ~ growing on a

An Experimental Testbed for Tactical Command and Control

“…2). Both MRG (21) and MDGI (11,25) are highly expressed in the fully differentiated lactating mammary gland and induce mammary differentiation. In the current study, we established MRG transgenic mouse under the promoter of mouse mammary tumor virus (MMTV) and investigated the role of MRG on mammary gland differentiation.…”

“…Studies of mouse and bovine MDGI suggest several functions of MDGI on growth and differentiation of mammary gland. MDGI specifically inhibit the growth of normal mouse mammary epithelial cells (MEC), and promote morphological differentiation: the appearance of bulbous alveolar end buds and formation of fully developed lobuloalveolar structures (7). Selective inhibition of endogenous MDGI expression in mouse MEC by use of antisense oligonucleotides suppresses alveolar budding and impairs ß-casein synthesis in organ cultures (7).…”

“…MDGI specifically inhibit the growth of normal mouse mammary epithelial cells (MEC), and promote morphological differentiation: the appearance of bulbous alveolar end buds and formation of fully developed lobuloalveolar structures (7). Selective inhibition of endogenous MDGI expression in mouse MEC by use of antisense oligonucleotides suppresses alveolar budding and impairs ß-casein synthesis in organ cultures (7). Increasing amounts of MDGI mRNA were detected in terminal parts of ducts and lobuloalveolar epithelial cells of differentiated glands and maximally expressed in the terminally differentiated state found just prior to lactation (8).…”

Breast Cancer Prevention by Hormonally Induced Mammary Gland Differentiation: The Role of a Novel Mammary Growth Inhibitor and Differentiation Factor MRG (Addendum)

“…Studies of mouse and bovine MDGI suggest several fimctions of MDGI on growth and differentiation of mammary gland. MDGI specifically inhibit the growth of normal mouse mammary epithelial cells (MEC), and promote morphological differentiation: the appearance of bulbous alveolar end buds and formation of fully developed lobuloalveolar structures (7). Selective inhibition of endogenous MDGI expression in mouse MEC by use of antisense oligonucleotides suppresses alveolar budding and impairs B-casein synthesis in organ cultures (7).…”

“…MDGI specifically inhibit the growth of normal mouse mammary epithelial cells (MEC), and promote morphological differentiation: the appearance of bulbous alveolar end buds and formation of fully developed lobuloalveolar structures (7). Selective inhibition of endogenous MDGI expression in mouse MEC by use of antisense oligonucleotides suppresses alveolar budding and impairs B-casein synthesis in organ cultures (7). Increasing amounts of MDGI mRNA were detected in terminal parts of ducts and lobuloalveolar epithelial cells of differentiated glands and maximally expressed in the terminally differentiated state found just prior to lactation (8).…”