title: Retinoic acid increases tyrosine phosphorylation of focal adhesion kinase and paxillin in MCF-7 human breast cancer cells.
abstract: Treatment of estrogen receptor (ER)-positive MCF-7 human breast cancer cells with retinoic acid (RA) inhibited cell growth and increased cell adhesion to fibronectin. In contrast, ER- MDA-MB-231 cells failed to respond. Western blot analysis showed that tyrosine phosphorylation of two major bands at Mr 125,000 and Mr 68,000 was induced by RA in ER+ MCF-7 human breast carcinoma cells. However, this induction was a late phenomenon detectable at 12 and 24 h, but not within 3 h. A similar increase of tyrosine phosphorylation by RA was observed in ER+ human breast cancer cell lines T-47D and ZR-75-1, but not in the ER- cell lines MDA-MB-231, MDA-MB-453, and MDA-MB-468. Focal adhesion kinase and paxillin, which localize in focal adhesion plaques and may play important roles in the integrin signaling pathway, were identified as the major proteins showing RA-induced tyrosine phosphorylation. The retinoid X receptor-selective compound SR11237 failed to induce tyrosine phosphorylation, indicating that retinoid X receptor activation is not involved in this phenomenon. In contrast, stable overexpression of a truncated RA receptor (RAR) alpha cDNA, RARalpha403, with strong RAR dominant negative activity prevented the increase in tyrosine phosphate, suggesting that RAR signaling is involved in RA-induced tyrosine phosphorylation. Tyrosine phosphorylation was induced the most by the RAR-alpha (193836), followed by RAR-gamma (194433), but was not significantly induced by RAR-gamma (193174)-selective retinoids. This study demonstrates a coordinated albeit relatively late effect of RA on cell adhesion and tyrosine phosphorylation in ER+ human breast cancer cells and suggests RAR-alpha as the major responsible retinoid receptor.
authors.affiliation: Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, Bethesda, Maryland 20892-4255, USA.
authors.forename: W Y
authors.initials: WY
authors.lastname: Zhu
authors.forename: C S
authors.initials: CS
authors.lastname: Jones
authors.forename: S
authors.initials: S
authors.lastname: Amin
authors.forename: K
authors.initials: K
authors.lastname: Matsukuma
authors.forename: M
authors.initials: M
authors.lastname: Haque
authors.forename: V
authors.initials: V
authors.lastname: Vuligonda
authors.forename: R A
authors.initials: RA
authors.lastname: Chandraratna
authors.forename: L M
authors.initials: LM
authors.lastname: De Luca
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D005260:Female; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006801:Humans; D051419:Paxillin; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology* / Q000627:therapeutic use; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D015815:Cell Adhesion Molecules; D003598:Cytoskeletal Proteins; C496061:PXN protein, human; D051419:Paxillin; D010750:Phosphoproteins; D018168:Receptors, Retinoic Acid; D014443:Tyrosine; D014212:Tretinoin; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human