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Gene Expression Profiling of Breast Cancer in Relation to Estrogen Receptor Status and Estrogen-Metabolizing Enzymes: Clinical Implications

¹ Department of Genetics, Institute of Cancer Research, Norwegian Radium Hospital; ² Department of Surgery, Ullevaal Hospital, Oslo, Norway; ³ Department of Oncology, Haukeland Hospital, Bergen, Norway; and ⁴ Department of Biochemistry, School of Medicine, Fujita Health University, Toyoake, Japan

Requests for reprints: Vessela N. Kristensen, Department of Genetics, Institute of Cancer Research, Norwegian Radium Hospital, Montebello 0310, Oslo, Norway. Phone: 47-22-93-44-17; Fax: 47-22-93-44-40; E-mail: nedelcheva.vessela{at}dnr.uio.no..

Interactions between luminal epithelial cells and their surrounding microenvironment govern the normal development and function of the mammary gland. Estradiol plays a key role in abnormal intracellular signaling, which contributes to the development and progression of breast tumors. The present article summarizes the results from a microarray whole genome gene expression analysis as well as a quantitative analysis of the mRNA expression of members of the estradiol metabolic and signaling pathways in the tumors of postmenopausal breast cancer patients. The analysis of the variation in whole genome gene expression resulted in a tumor classification comprising several distinct groups with distinct expression of the estrogen receptor (ER). The parallel study on the expression of only nine mRNA transcripts of members of the estradiol pathways resulted in two main clusters, representing ER– and ER tumors. The mRNA expression of the estradiol-metabolizing enzymes did not follow the expression of the ER in all cases, leading to the recognition of several further subclasses of tumors. When the tumor classes obtained by whole genome gene expression analysis were compared with those obtained by independent quantitation of the estradiol-metabolizing enzymes, a statistically significant association between both classification groups was observed. These findings point to a possible association between development of a tumor with a particular expression profile and its capacity to synthesize estradiol as measured by the expression of the transcripts for the necessary key enzymes. Further, whole genome expression patterns were studied in 12 patients treated with anastrozole. Using significance analysis of microarrays, we identified 298 genes significantly differently expressed between partial response and progressive disease groups.

Key Words: estradiol metabolism • SNP • stage of disease • clustering analysis

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