title: Significance of mismatch repair protein expression in the chemotherapeutic response of sporadic invasive ductal carcinoma of the breast.
abstract: The mismatch repair (MMR) gene plays a key role in the correction of DNA damage, and the loss of MMR has been implicated in resistance to a variety of chemotherapeutic drugs. The purpose of this study was to assess whether the reduced expression of hMLH1 and/or hMSH2 affects the chemotherapeutic responsiveness of sporadic invasive ductal carcinoma of the breast. Immunohistochemical studies were performed on 71 histologic specimens of breast cancer taken from the patients treated with surgery and subsequent cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) or cyclophosphamide, Adriamycin, and 5-fluorouracil (CAF) chemotherapy for stage II or III primary breast cancer. Single-strand conformational polymorphism polymerase chain reaction (PCR-SSCP) and sequencing were carried out in 16 patients. A combined immunoreactivity score (hMLH1-IS and hMSH2-IS) was calculated by multiplying the staining grade by the intensity score. Positive expression (>4) of hMLH1-IS and hMSH2-IS were 57.7% and 60.6%, respectively, and complete losses of hMLH1 and hMSH2 were observed in 4.2% of patients. Of the patients with advanced cancer with lymph node metastasis, those having a low hMLH1-IS had a significantly higher failure rate with the CMF regimen than those having a high hMLH1-IS (p = 0.03). No significant difference was noted in chemotherapeutic response according to hMLH1 and hMSH2 expression in the CAF group. Both hMLH1-IS (p = 0.03) and progesterone receptor (PR) status (p = 0.03) were well correlated with CMF chemotherapy response in breast cancers with lymph node metastasis. Our study shows that a lack of hMLH1 expression may play a role in drug resistance, especially in the CMF group, and immunohistochemical assay for MMR protein can be used as a convenient tool for evaluating chemotherapeutic response in patients with breast cancer.
authors.affiliation: Department of Surgery, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Korea. brdrson@korea.com
authors.forename: Byung Ho
authors.initials: BH
authors.lastname: Son
authors.forename: Sei Hyun
authors.initials: SH
authors.lastname: Ahn
authors.forename: Chang Dae
authors.initials: CD
authors.lastname: Ko
authors.forename: In Wha
authors.initials: IW
authors.lastname: Ka
authors.forename: Gyung Yeop
authors.initials: GY
authors.lastname: Gong
authors.forename: Jin Cheon
authors.initials: JC
authors.lastname: Kim
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins; D002945:Cisplatin / Q000008:administration & dosage; D003520:Cyclophosphamide / Q000008:administration & dosage; D004268:DNA-Binding Proteins; D004317:Doxorubicin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008207:Lymphatic Metastasis; D008727:Methotrexate / Q000008:administration & dosage; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009363:Neoplasm Proteins / Q000378:metabolism*; D009367:Neoplasm Staging; D009687:Nuclear Proteins; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D011379:Prognosis; D011506:Proteins / Q000378:metabolism*; D011518:Proto-Oncogene Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D004317:Doxorubicin; D003520:Cyclophosphamide; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D002945:Cisplatin; D005472:Fluorouracil; D008727:Methotrexate