title: Prediction of breast cancer sensitivity to neoadjuvant chemotherapy based on status of DNA damage repair proteins.
abstract: BACKGROUND
  Various agents used in breast cancer chemotherapy provoke DNA double-strand breaks (DSBs). DSB repair competence determines the sensitivity of cells to these agents whereby aberrations in the repair machinery leads to apoptosis. Proteins required for this pathway can be detected as nuclear foci at sites of DNA damage when the pathway is intact. Here we investigate whether focus formation of repair proteins can predict chemosensitivity of breast cancer.
  
  
  METHODS
  Core needle biopsy specimens were obtained from sixty cases of primary breast cancer before and 18-24 hours after the first cycle of neoadjuvant epirubicin plus cyclophosphamide (EC) treatment. Nuclear focus formation of DNA damage repair proteins was immunohistochemically analyzed and compared with tumor response to chemotherapy.
  
  
  RESULTS
  EC treatment induced nuclear foci of gammaH2AX, conjugated ubiquitin, and Rad51 in a substantial amount of cases. In contrast, BRCA1 foci were observed before treatment in the majority of the cases and only decreased after EC in thirteen cases. The presence of BRCA1-, gammaH2AX-, or Rad51-foci before treatment or the presence of Rad51-foci after treatment was inversely correlated with tumor response to chemotherapy. DNA damage response (DDR) competence was further evaluated by considering all four repair indicators together. A high DDR score significantly correlated with low tumor response to EC and EC + docetaxel whereas other clinicopathological factors analyzed did not.
  
  
  CONCLUSIONS
  High performing DDR focus formation resulted in tumor resistance to DNA damage-inducing chemotherapy. Our results suggested an importance of evaluation of DDR competence to predict breast cancer chemosensitivity, and merits further studying into its usefulness in exclusion of non-responder patients.
authors.affiliation: Division of Breast and Endocrine Surgery, Department of Surgery, St, Marianna University School of Medicine, Kawasaki, Japan. hiddie_vr4@hotmail.com
authors.forename: Hideki
authors.initials: H
authors.lastname: Asakawa
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Koizumi
authors.forename: Ayaka
authors.initials: A
authors.lastname: Koike
authors.forename: Makiko
authors.initials: M
authors.lastname: Takahashi
authors.forename: Wenwen
authors.initials: W
authors.lastname: Wu
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Iwase
authors.forename: Mamoru
authors.initials: M
authors.lastname: Fukuda
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Ohta
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019313:BRCA1 Protein / Q000378:metabolism; D001707:Biopsy, Needle; D001940:Breast / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D017024:Chemotherapy, Adjuvant; D003520:Cyclophosphamide / Q000008:administration & dosage; D004249:DNA Damage; D004260:DNA Repair; D000077143:Docetaxel; D015251:Epirubicin / Q000008:administration & dosage; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D017063:Outcome Assessment, Health Care / Q000379:methods; D011237:Predictive Value of Tests; D011379:Prognosis; D011506:Proteins / Q000378:metabolism*; D051135:Rad51 Recombinase / Q000378:metabolism; D043823:Taxoids / Q000008:administration & dosage; D025801:Ubiquitin / Q000737:chemistry / Q000378:metabolism
chemical_list: D019313:BRCA1 Protein; C468783:H2AX protein, human; D006657:Histones; D011506:Proteins; D043823:Taxoids; D025801:Ubiquitin; D000077143:Docetaxel; D015251:Epirubicin; D003520:Cyclophosphamide; C495153:RAD51 protein, human; D051135:Rad51 Recombinase