Developmental regulation of mammary-derived growth inhibitor expression in bovine mammary tissue.

Abstract

Abstract. The cDNA for a previously described growth inhibitor, designated as mammary-derived growth inhibitor (MDGI) (Grosse, R., and P. Langen. 1989. In Handbook of Experimental Pharmacology. In press) has been cloned from a plasmid library which was derived from terminally differentiated bovine mammary gland.Sequencing of the cDNA showed an open reading frame coding for a protein of 133 amino acids. In six positions differences were found between the sequence determined from the cDNA and that determined previously by amino acid sequence analysis. Northern blot analysis revealed abundant MDGI mRNA in the terminally differentiated mammary gland, whereas in virgin gland, liver or pancreas transcripts were not expressed. By use of in situ hybridization technique transcription of MDGI in the developing bovine mammary gland was analyzed.Increasing amounts of MDGI mRNA were detected in the epithelial cells of embryonic mammary rudiment, in the epithelium of developing lobules and in terminal parts of ducts and lobuloalveolar epithelial cells of differentiated glands. There was a geographical gradient of MDGI mRNA concentration in bovine mammary gland reaching a maximum in the proximal parts of the tissue. An immunohistochemical analysis with different polyclonal and peptide directed antibodies against MDGI confirmed the in situ hybridization data with respect to the tissue-specific and differentiation-dependent MDGI expression in bovine mammary gland. The results suggest a close relationship between MDGI transcription and developmental processes in the normal bovine mammary gland.

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

“…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). MDGI expression in mouse mammary epithelium cells is hormonally regulated (9)(10).…”

“…2). Both MRG (21) and MDGI (11,25) are highly expressed in the fully differentiated lactating mammary gland and induce mammary differentiation. 3).…”

Mammary-derived growth inhibitor (MDGI) interacts with integrin α-subunits and suppresses integrin activity and invasion

“…However, MDGI lacks an N-terminal signal peptide and it is not clear whether it or its fragments are secreted in vivo (Clark et al, 2000). The expression of MDGI mRNA is hormonally regulated in breast epithelial cells during development and is highly expressed at the time of maximal differentiated function (just before lactation) (Kurtz et al, 1990). Interestingly, antiestrogen therapy can stabilize MDGI mRNA in vitro (Huynh and Pollak, 1997) suggesting that MDGI may also be involved in anticancer activity of antiestrogens.…”

Breast cancer growth inhibition by delivery of the MDGI-derived peptide P108

“…MDGI was isolated from lactating mammary gland in a puri®cation scheme aimed at the identi®cation of growth inhibitory factors of the normal mammary gland (Boehmer et al, 1987). MDGI is tightly regulated in the course of mammary gland morphogenesis, with highest protein levels during late pregnancy and lactation (Kurtz et al, 1990), and expression is downregulated in a majority of human breast cancer samples, indicating tumor suppressor functions (Huynh et al, 1995(Huynh et al, , 1996Zschiesche et al, 1995). MDGI induced functional di erentiation and suppressed ductal growth in primed mammary gland organ cultures (Yang et al, 1995), and expression of cytoplasmic MDGI in MCF-7 cells reduced tumor growth (Huynh et al, 1995).…”