Cripto: roles in mammary cell growth, survival, differentiation and transformation.
Cripto-1 (Cr-1) protein, encoded by the teratocarcinoma-derived growth factor gene (TDGF-1), is highly correlated with transformation in breast cancer. Eighty-two percent of breast carcinomas express Cr-1 whereas it is undetected in normal human breast tissue. We confirmed and extended findings that Cr-1 protein is expressed during the pregnancy and lactating stages of normal murine mammary glands but is barely detectable in glands from virgin animals and is undetectable in involuted glands. Cr-1 was found to be expressed in CID 9 cells, a line of mammary epithelial cells derived from 14.5 day pregnant mice and we have used these cells to investigate the roles of this gene. Exogenous mouse Cr-1 expression from a retroviral vector caused CID 9 cells to grow at an increased rate and to increased cell densities compared to parental and control cells. CID 9 cells overexpressing Cr-1 did not differentiate efficiently. Infection of CID 9 cells with a Cr-1 antisense vector caused these cells to change in morphology, to grow slowly, to undergo apoptosis at a higher rate and to achieve lower saturation densities but the cells were still capable of differentiating. We concluded that Cr-1 is an autocrine growth factor for normal breast cells, that when over-expressed stimulates excessive cell proliferation at the expense of differentiation. In transplantation studies, Cr-1 over-expression stimulated the growth and survival of mammary cells, but did not stimulate tumorigenesis in vivo.
Niemeyer
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The Burnham Institute, La Jolla Cancer Research Center, 10901 North Torrey Pines Road, La Jolla, California 92037, USA.
Persico
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Adamson
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D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D004815:Epidermal Growth Factor; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006133:Growth Substances / Q000235:genetics / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D008321:Mammary Glands, Animal / Q000187:drug effects* / Q000378:metabolism; D008562:Membrane Glycoproteins; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics* / Q000494:pharmacology*; D016376:Oligonucleotides, Antisense / Q000235:genetics; D011247:Pregnancy; D014162:Transfection
D006133:Growth Substances; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D016376:Oligonucleotides, Antisense; C489450:Tdgf1 protein, mouse; D004815:Epidermal Growth Factor