Cyclooxygenase-2 expression in human breast cancers and adjacent ductal carcinoma in situ

Cancer Res. 2002 Mar 15;62(6):1676-81.

Abstract

Cyclooxygenase-2 (COX-2) is an inducible enzyme that converts arachidonic acid to prostaglandins. Overexpression of the COX-2 gene in mammary glands of transgenic mice was sufficient to induce tumorigenesis. We analyzed COX-2 expression in human breast cancers (and breast cancer cell lines) and adjacent ductal carcinoma in situ (DCIS) as well as its association with HER2/neu and clinicopathological variables. Archival primary breast carcinomas (n = 57), adjacent DCIS (n = 14) and DCIS alone (n = 2) were analyzed for COX-2 and HER2 expression by immunohistochemistry using specific monoclonal antibodies. An immunohistochemical scoring system was used. HER2 gene amplification had been analyzed previously by fluorescence in situ hybridization (n = 20). Histology of carcinomas included infiltrating ductal (n = 44), lobular (n = 2), and other (n = 7). Frozen breast cancers and adjacent normal tissue pairs (n = 9) were analyzed for COX-2 mRNA by reverse transcription-PCR. COX-2 and HER2 expression were also analyzed in human breast cancer cell lines (MCF-7, MCF-7/HER2, SK-BR-3, and MDA-MB-231) by immunoblotting. Cytoplasmic COX-2 expression was detected at an intermediate or high level in epithelial cells in 18 of 42 (43%) invasive breast cancers and in 10 of 16 (63%) cases of DCIS. Normal-appearing breast epithelia adjacent to cancer expressed COX-2 in 81% of cases and was generally focal and of similar or decreased intensity relative to adjacent neoplastic epithelia. COX-2 mRNA was detected in all samples analyzed by reverse transcription-PCR and was increased in eight of nine breast cancers relative to paired normal tissue. In archival tumors, no significant correlation was found between COX-2 and HER2 expression/amplification and clinicopathological variables. COX-2 expression was induced in MCF-7 cells stably transfected with HER2, in contrast to parental MCF-7 cells, and was detected in MDA-MB-231, but not SK-BR-3 cells. COX-2 is frequently overexpressed in invasive breast cancers and in adjacent DCIS and, thus, may be an early event in mammary tumorigenesis. Forced HER2 expression in MCF-7 cells was shown to up-regulate COX-2, although no association was found in human tumors. Our results suggest that nonsteroidal anti-inflammatory drugs and selective COX-2 inhibitors may be useful in the chemoprevention and therapy of human breast cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Breast Neoplasms / enzymology*
  • Breast Neoplasms / pathology
  • Carcinoma in Situ / enzymology*
  • Carcinoma in Situ / pathology
  • Carcinoma, Ductal, Breast / enzymology*
  • Carcinoma, Ductal, Breast / pathology
  • Cyclooxygenase 2
  • Female
  • Gene Amplification
  • Humans
  • Isoenzymes / biosynthesis*
  • Isoenzymes / genetics
  • Membrane Proteins
  • Middle Aged
  • Neoplasm Staging
  • Prostaglandin-Endoperoxide Synthases / biosynthesis*
  • Prostaglandin-Endoperoxide Synthases / genetics
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Receptor, ErbB-2 / biosynthesis
  • Receptor, ErbB-2 / genetics
  • Receptors, Estrogen / biosynthesis
  • Receptors, Progesterone / biosynthesis
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Cells, Cultured

Substances

  • Isoenzymes
  • Membrane Proteins
  • RNA, Messenger
  • Receptors, Estrogen
  • Receptors, Progesterone
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases
  • Receptor, ErbB-2