title: Stress hormones reduce the efficacy of paclitaxel in triple negative breast cancer through induction of DNA damage.
abstract: BACKGROUND
  The mechanisms by which stress hormones impact triple-negative breast cancer (TNBC) etiology and treatment are unclear. We have previously shown that stress hormones, cortisol, and catecholamines induce rapid DNA damage and impact DNA repair in NIH 3T3 fibroblasts. This study investigates whether stress hormones increase DNA damage in breast cancer cells and if this impacts drug efficacy.
  
  
  METHODS
  We first screened a panel of 39 breast cancer cell lines for expression of adrenergic and glucocorticoid receptors and examined if stress hormones induce DNA damage and alter cell cycle regulation in vitro. A TNBC xenograft model was used to assess the impact of restraint stress on tumour growth and chemosensitivity to paclitaxel.
  
  
  RESULTS
  We found that stress hormones induced DNA damage, phosphorylation of ATR, which was accompanied by an up-regulation of the G1 cell kinase inhibitor p21 and a cell cycle halt of TNBCs in the G1 phase. p21 knockdown abrogated G1 arrest by stress hormones. We also demonstrated that stress significantly decreased efficacy of paclitaxel.
  
  
  CONCLUSIONS
  We describe a novel mechanism through which stress hormones can induce drug resistance to paclitaxel, which may have profound implications for treating drug resistance in patients with TNBC.
authors.affiliation: Womens Cancer Research Centre, Pittsburgh, PA 15213, USA.
authors.forename: A
authors.initials: A
authors.lastname: Reeder
authors.affiliation: 1] Womens Cancer Research Centre, Pittsburgh, PA 15213, USA [2] Department of Pharmacology and Chemical Biology, Pittsburgh, PA 15213, USA [3] University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.
authors.forename: M
authors.initials: M
authors.lastname: Attar
authors.affiliation: Womens Cancer Research Centre, Pittsburgh, PA 15213, USA.
authors.forename: L
authors.initials: L
authors.lastname: Nazario
authors.affiliation: 1] Womens Cancer Research Centre, Pittsburgh, PA 15213, USA [2] Department of Pharmacology and Chemical Biology, Pittsburgh, PA 15213, USA.
authors.forename: C
authors.initials: C
authors.lastname: Bathula
authors.affiliation: Womens Cancer Research Centre, Pittsburgh, PA 15213, USA.
authors.forename: A
authors.initials: A
authors.lastname: Zhang
authors.affiliation: Womens Cancer Research Centre, Pittsburgh, PA 15213, USA.
authors.forename: D
authors.initials: D
authors.lastname: Hochbaum
authors.affiliation: Womens Cancer Research Centre, Pittsburgh, PA 15213, USA.
authors.forename: E
authors.initials: E
authors.lastname: Roy
authors.affiliation: 1] Womens Cancer Research Centre, Pittsburgh, PA 15213, USA [2] University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA [3] Biostatistics Facility Department of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: K L
authors.initials: KL
authors.lastname: Cooper
authors.affiliation: 1] Womens Cancer Research Centre, Pittsburgh, PA 15213, USA [2] Department of Pharmacology and Chemical Biology, Pittsburgh, PA 15213, USA [3] University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.
authors.forename: S
authors.initials: S
authors.lastname: Oesterreich
authors.affiliation: 1] Womens Cancer Research Centre, Pittsburgh, PA 15213, USA [2] University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA [3] Department of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: N E
authors.initials: NE
authors.lastname: Davidson
authors.affiliation: 1] Womens Cancer Research Centre, Pittsburgh, PA 15213, USA [2] Department of Pharmacology and Chemical Biology, Pittsburgh, PA 15213, USA [3] University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Neumann
authors.affiliation: 1] Womens Cancer Research Centre, Pittsburgh, PA 15213, USA [2] Department of Pharmacology and Chemical Biology, Pittsburgh, PA 15213, USA [3] University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA [4] University of Brighton, School of Pharmacy and Biosciences, University of Brighton, Brighton BN2 4GJ, UK.
authors.forename: M S
authors.initials: MS
authors.lastname: Flint
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002395:Catecholamines / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects*; D004260:DNA Repair / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D017239:Paclitaxel / Q000494:pharmacology*; D011960:Receptors, Estrogen / Q000378:metabolism; D015398:Signal Transduction; D013312:Stress, Physiological / Q000187:drug effects*; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D002395:Catecholamines; D011960:Receptors, Estrogen; D017239:Paclitaxel; D006854:Hydrocortisone