Functional genetic polymorphisms in the aromatase gene CYP19 vary the response of breast cancer patients to neoadjuvant therapy with aromatase inhibitors

Liewei Wang, Katarzyna A. Ellsworth, Irene Moon, Linda L. Pelleymounter, Bruce W. Eckloff, Yvette N. Martin, Brooke L. Fridley, Gregory D. Jenkins, Anthony Batzler, Vera J. Suman, Saranya Ravi, J. Michael Dixon, William R. Miller, Eric D. Wieben, Aman Buzdar, Richard M. Weinshilboum, James N. Ingle

Research output: Contribution to journalArticlepeer-review

85 Scopus citations

Abstract

Aromatase (CYP19) is a critical enzyme in estrogen biosynthesis and aromatase inhibitors (AI) are employed widely for endocrine therapy in postmenopausal women with breast cancer. We hypothesized that single nucleotide polymorphisms (SNPs) in the CYP19 gene may alter the effectiveness of AI therapy in the neoadjuvant setting. Genomic DNA was obtained for sequencing from 52 women pre-AI and post-AI treatment in this setting. Additionally, genomic DNA obtained from 82 samples of breast cancer and 19 samples of normal breast tissue was subjected to resequencing. No differences in CYP19 sequence were observed between tumor and germ-line DNA in the same patient. A total of 48 SNPs were identified including 4 novel SNPs when compared with previous resequencing data. For genotype-phenotype association studies, we determined the levels of aromatase activity, estrone, estradiol, and tumor size in patients pre-AI and post-AI treatment. We defined two tightly linked SNPs (rs6493497 and rs7176005 in the 5′-flanking region of CYP19 exon 1.1) that were significantly associated with a greater change in aromatase activity after AI treatment. In a follow-up study of 200 women with early-stage breast cancer who were treated with adjuvant anastrozole, these same two SNPs were also associated with higher plasma estradiol levels in patients pre-AI and post-AI treatment. Electrophoretic mobility shift and reporter gene assays confirmed likely functional effects of these two SNPs on transcription of CYP19. Our findings indicate that two common genetic polymorphisms in the aromatase gene CYP19 vary the response of breast cancer patients to aromatase inhibitors.

Original languageEnglish (US)
Pages (from-to)319-328
Number of pages10
JournalCancer research
Volume70
Issue number1
DOIs
StatePublished - Jan 1 2010

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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