title: Anti-tumor effects of retinoids combined with trastuzumab or tamoxifen in breast cancer cells: induction of apoptosis by retinoid/trastuzumab combinations.
abstract: BACKGROUND
  HER2 and estrogen receptor (ER) are important in breast cancer and are therapeutic targets of trastuzumab (Herceptin) and tamoxifen, respectively. Retinoids inhibit breast cancer growth, and modulate signaling by HER2 and ER. We hypothesized that treatment with retinoids and simultaneous targeting of HER2 and/or ER may have enhanced anti-tumor effects.
  
  
  METHODS
  The effects of retinoids combined with trastuzumab or tamoxifen were examined in two human breast cancer cell lines in culture, BT474 and SKBR3. Assays of proliferation, apoptosis, differentiation, cell cycle distribution, and receptor signaling were performed.
  
  
  RESULTS
  In HER2-overexpressing/ER-positive BT474 cells, combining all-trans retinoic acid (atRA) with tamoxifen or trastuzumab synergistically inhibited cell growth, and altered cell differentiation and cell cycle. Only atRA/trastuzumab-containing combinations induced apoptosis. BT474 and HER2-overexpressing/ER-negative SKBR3 cells were treated with a panel of retinoids (atRA, 9-cis-retinoic acid, 13-cis-retinoic acid, or N-(4-hydroxyphenyl) retinamide (fenretinide) (4-HPR)) combined with trastuzumab. In BT474 cells, none of the single agents except 4-HPR induced apoptosis, but again combinations of each retinoid with trastuzumab did induce apoptosis. In contrast, the single retinoid agents did cause apoptosis in SKBR3 cells; this was only modestly enhanced by addition of trastuzumab. The retinoid drug combinations altered signaling by HER2 and ER. Retinoids were inactive in trastuzumab-resistant BT474 cells.
  
  
  CONCLUSIONS
  Combining retinoids with trastuzumab maximally inhibits cell growth and induces apoptosis in trastuzumab-sensitive cells. Treatment with such combinations may have benefit for breast cancer patients.
authors.affiliation: Department of Internal Medicine (Section of Medical Oncology), Yale Cancer Center and Smilow Cancer Hospital at Yale-New-Haven Hospital, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA.
authors.forename: Debbie C
authors.initials: DC
authors.lastname: Koay
authors.forename: Cynthia
authors.initials: C
authors.lastname: Zerillo
authors.forename: Murli
authors.initials: M
authors.lastname: Narayan
authors.forename: Lyndsay N
authors.initials: LN
authors.lastname: Harris
authors.forename: Michael P
authors.initials: MP
authors.lastname: DiGiovanna
mesh_terms: D000077556:Alitretinoin; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004965:Estrogen Antagonists / Q000494:pharmacology; D005260:Female; D006801:Humans; D015474:Isotretinoin / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D012176:Retinoids / Q000494:pharmacology*; D013629:Tamoxifen / Q000494:pharmacology*; D000068878:Trastuzumab; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D000077556:Alitretinoin; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D004965:Estrogen Antagonists; D015474:Isotretinoin; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D012176:Retinoids; D013629:Tamoxifen; D000068878:Trastuzumab; D014212:Tretinoin