Abstract
We showed earlier that cellular retinol-binding protein (CRBP) expression is downregulated in a subset of human breast cancers. We have now investigated the outcome of ectopic CRBP expression in MTSV1-7 cells, a SV40 T antigen-transformed human breast epithelial cell line devoid of endogenous CRBP expression. We found that: (i) CRBP did not inhibit adherent cell growth but suppressed foci formation in post-confluent cultures and colony formation in soft agar; (ii) this effect was due to CRBP inhibition of cell survival, as demonstrated by viability and TUNEL assays of cells in soft-agar or plated on polyHEMA-coated dishes; (iii) CRBP inhibited protein kinase B/Akt activation in cells in suspension but not in adherent cells and the CRBP suppression of anchorage-independent growth was mimicked by cell treatment with the phosphatidylinositol-3 kinase (PI3K) inhibitor LY294002; (iv) CRBP enhanced retinyl ester formation and storage but did not regulate retinoic acid synthesis or retinoic acid receptor activity. Ectopic CRBP-mediated inhibition of anchorage-independent cell survival and colony formation in the absence of significantly altered responses to either retinol or retinoic acid was also documented in T47D human breast cancer cells. In conclusion, the data suggest two novel and linked CRBP functions in mammary epithelial cells: inhibition of the PI3K/Akt survival pathway and suppression of anchorage-independent growth.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Agar
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Apoptosis / drug effects*
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Breast / cytology
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Breast Neoplasms / pathology*
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Carrier Proteins / metabolism
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Cell Adhesion
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Cell Division / drug effects
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Cell Line, Transformed
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Cell Transformation, Viral
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Chromones / pharmacology
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Contact Inhibition
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Enzyme Activation / drug effects
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Enzyme Inhibitors / pharmacology
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Fatty Acid-Binding Protein 7
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Fatty Acid-Binding Proteins
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Female
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Humans
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Morpholines / pharmacology
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Neoplasm Proteins / metabolism
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Protein Serine-Threonine Kinases*
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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Receptors, Retinoic Acid / metabolism
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Retinol-Binding Proteins / deficiency
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Retinol-Binding Proteins / genetics
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Retinol-Binding Proteins / pharmacology*
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Retinol-Binding Proteins, Cellular
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Signal Transduction / drug effects
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Simian virus 40 / physiology
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Tretinoin / metabolism
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Tretinoin / pharmacology
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Tumor Stem Cell Assay
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Tumor Suppressor Proteins*
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Vitamin A / pharmacology
Substances
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Carrier Proteins
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Chromones
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Enzyme Inhibitors
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FABP7 protein, human
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Fatty Acid-Binding Protein 7
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Fatty Acid-Binding Proteins
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Morpholines
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Neoplasm Proteins
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Phosphoinositide-3 Kinase Inhibitors
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Proto-Oncogene Proteins
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Receptors, Retinoic Acid
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Retinol-Binding Proteins
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Retinol-Binding Proteins, Cellular
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Tumor Suppressor Proteins
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Vitamin A
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Tretinoin
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Agar
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AKT1 protein, human
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt