Heterogeneity of breast cancer metastases: Comparison of therapeutic target expression and promoter methylation between primary tumors and their multifocal metastases Journal Article
| Authors: | Wu, J. M.; Fackler, M. J.; Halushka, M. K.; Molavi, D. W.; Taylor, M. E.; Wei, W. T.; Griffin, C.; Fetting, J.; Davidson, N. E.; De Marzo, A. M.; Hicks, J. L.; Chitale, D.; Ladanyi, M.; Sukumar, S.; Argani, P. |
| Article Title: | Heterogeneity of breast cancer metastases: Comparison of therapeutic target expression and promoter methylation between primary tumors and their multifocal metastases |
| Abstract: | Purpose: A comprehensive comparison of biomarker expression between patients' primary breast carcinoma (PBC) and their metastatic breast carcinomas (MBC) has not been done. Experimental Design: We did rapid autopsies (postmortem intervals, 1-4 hours) on 10 consenting patients who died of MBC. We constructed single-patient tissue microarrays from the patients' archived PBC and multiple different MBCs harvested at autopsy, which were immunohistochemically labeled for multiple biomarkers. Methylation of multiple gene promoters was assessed quantitatively on dissected PBC and MBC samples. Results: Extensive heterogeneity was observed between PBC and their paired MBC, as well as among multiple MBC from the same patient. Estrogen and progesterone receptors tended to be uniformly down-regulated inmetastases. E-cadherin was down-regulated in a subset of the MBC of one case. Variable overexpression in MBC compared with the PBC was observed for cyclooxygenase-2 (five cases), epidermal growth factor receptor (EGFR; four cases), MET (four cases), and mesothelin (four cases). No case strongly overexpressed HER-2/neu by immunohistochemistry, but eight cases showed variable protein expression ranging from negative to equivocal (2+) in different MBC. In one case, variable low-level HER-2/neu gene amplification was found. EGFR and MET overexpression were restricted to the four basal-type cancers. EGFR protein overexpression did not correlate with EGFR gene amplification. Multigene promoter hypermethylation of RASSF1a, HIN1, cyclin D2, Twist, estrogen receptor α, APC1, and RARβ was overall very similar in the PBC and all MBCs in all cases. Conclusions: Therapeutic targets identified in the PBC or even some MBC may not reflect targets present in all metastatic sites. © 2008 American Association for Cancer Research. |
| Keywords: | immunohistochemistry; protein expression; middle aged; primary tumor; unclassified drug; methylation; biological marker; metastasis; gene amplification; gene expression; epidermal growth factor receptor; epidermal growth factor receptor 2; tumor markers, biological; breast neoplasms; uvomorulin; dna methylation; cyclooxygenase 2; breast carcinoma; neoplasm metastasis; binding protein; tissue array analysis; down regulation; tissue microarray; progesterone receptor; autopsy; transcription factor twist; mesothelin; cyclin d2; ras association domain family protein 1a; estrogen receptor alpha; promoter regions (genetics); protein apc1; protein hin1 |
| Journal Title: | Clinical Cancer Research |
| Volume: | 14 |
| Issue: | 7 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2008-04-01 |
| Start Page: | 1938 |
| End Page: | 1946 |
| Language: | English |
| DOI: | 10.1158/1078-0432.ccr-07-4082 |
| PUBMED: | 18381931 |
| PROVIDER: | scopus |
| PMCID: | PMC2965068 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 46" - "Export Date: 17 November 2011" - "CODEN: CCREF" - "Source: Scopus" |
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