Roles of mismatch repair proteins hMSH2 and hMLH1 in the development of sporadic breast cancer.
Defects in mismatch repair (MMR) genes, particularly the hMSH2 and hMLH1 genes, are associated with a variety of cancers including sporadic breast cancer. However, whether or not patient clinical background, e.g. age, progesterone receptor (PR), estrogen receptor (ER), tumor progression and stage, chemotherapy history, and menopausal status, influences MMR status is not understood. To address these issues, 83 archival breast cancer specimens were examined for expression of hMSH2 and hMLH1 by immunohistochemistry and the relationship between MMR protein expression and patient clinical background was analyzed. We detected lack of or reduced expression of hMSH2 and hMLH1 in 23 (27.7%) and 26 cases (31.3%), respectively, and hypermethylation of the hMLH1 promoter accounted for the majority of the cases with reduced expression of hMLH1. Statistical analysis revealed that (i) reduced expression of hMLH1 and hMSH2 seemed to confer advantage for the progression of breast tumors to more advanced stages; (ii) attenuated expression of hMLH1 correlated with history of chemotherapy, but not with age, menopause, or the status of PR and ER; (iii) hypermethylation of the hMLH1 promoter was linked with clinical stage and lymphatic metastasis. These analyses indicate that defective expression of MMR genes is closely associated with the development of sporadic breast cancer.
Murata
Hiroaki
H
Department of Pathology and Laboratory Medicine, University of Kentucky Medical Center, Suite MS117, 800 Rose Street, Lexington, KY 40536, USA.
Khattar
Nada H
NH
Gu
Liya
L
Li
Guo-Min
GM
D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000737:chemistry / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D002352:Carrier Proteins; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000032:analysis / Q000502:physiology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009363:Neoplasm Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000502:physiology*; D011960:Receptors, Estrogen / Q000032:analysis
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D011960:Receptors, Estrogen; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein