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Published on: October 6, 2009
Characterization of mammary-derived growth factor 1 receptors and response in human mammary epithelial cell lines
M Bano1, W R Kidwell, M E Lippman
1Lombardi Cancer Research Center, Georgetown University, Washington, D.C. 20007.
Insights
Mammary-derived growth factor 1 (MDGF1) stimulates growth and collagen synthesis in specific human breast cells. MDGF1 binds to receptors on responsive cell lines, indicating a role in mammary cell biology.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Mammary-derived growth factor 1 (MDGF1) is a 62 kDa protein purified from human milk.
- Its N-terminal sequence shows no homology to known growth factors.
- The biological roles and binding characteristics of MDGF1 remain largely uncharacterized.
Purpose of the Study:
- To investigate the biological effects of MDGF1 on normal and cancerous human mammary epithelial cells.
- To identify and characterize binding sites for MDGF1 on these cell lines.
- To explore the potential role of MDGF1 receptors in mammary cell function.
Main Methods:
- Cell proliferation assays using various human mammary cell lines (MCF-7, ZR75-1, T47-D, MDA-MB 231, MDA-MB 468, 184, 184A1N4).
- Collagen IV synthesis assays.
- Radioligand binding studies using iodinated MDGF1 (125I-MDGF1).
- Cross-linking experiments to identify MDGF1-binding proteins.
Main Results:
- MDGF1 (10-25 ng/ml) stimulated MCF-7 cell growth by 50% and collagen IV synthesis by 40%.
- MDGF1 showed differential effects on other cell lines, including biphasic effects on MDA-MB 468 cells and growth enhancement of normal and immortalized mammary epithelial cells.
- Transformation of mammary cells reduced their sensitivity to MDGF1.
- MDGF1 bound to moderate affinity sites (KD = 6 x 10(-9) M) on responsive cells (MCF-7, MDA-MB 468, 184A1N4).
- Cross-linking identified a ~180-200 kDa binding protein in responsive cell lines.
Conclusions:
- Human mammary epithelial cells possess specific receptors for MDGF1.
- MDGF1 influences the growth and extracellular matrix production of certain mammary cell types.
- The identified binding protein likely represents the MDGF1 receptor.
Abstract:
Mammary-derived growth factor 1 (MDGF1, with a molecular mass of 62 kDa and pI of 4.8) has been purified from human milk (Bano, M., Salomon, D. S., and Kidwell, W. R. (1985) J. Biol. Chem. 260, 5745-5752). N-terminal sequence of 18 amino acids showed no homology to any known growth promoting peptides. The present study was carried out to evaluate the biological effects of and binding sites for MDGF1 on normal human and breast cancer cell lines. At a concentration of 10-25 ng/ml the factor stimulated the growth of estrogen receptor-positive MCF-7 human breast cancer cells by 50% and also stimulated the synthesis of collagen IV by 40%. It did not have any effect on ZR75-1, T47-D, and MDA-MB 231 cells. The factor showed a biphasic effect on the estrogen receptor-negative MDA-MB 468 cells at concentrations above 5 ng/ml. The growth of normal human mammary epithelial cells (184 strain) was enhanced by 35%, whereas immortalized non-tumorigenic 184A1N4 human mammary epithelial cells were stimulated by about 60-70%. However, transformation of these cells by SV40-T, v-Ha-ras, or v-mos desensitized them to MDGF1. Iodinated MDGF1 binds to moderate affinity sites on the responsive MCF-7, MDA-MB 468, and 184A1N4 cell lines (KD = 6 x 10(-9) M). Cross-linking of 125I-MDGF1 to binding sites revealed the presence of a major band of molecular mass of approximately 180-200 kDa in MCF-7 and MDA-MB 468 cell lines. Labeling of this band was inhibited by excess unlabeled MDGF1. These data suggest that human mammary epithelial cell lines possess receptors for MDGF1.
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