Functional genetic polymorphisms in the aromatase gene CYP19 vary the response of breast cancer patients to neoadjuvant therapy with aromatase inhibitors.
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.
Wang
Liewei
L
Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota 55905, USA. wang.liewei@mayo.edu
Ellsworth
Katarzyna A
KA
Moon
Irene
I
Pelleymounter
Linda L
LL
Eckloff
Bruce W
BW
Martin
Yvette N
YN
Fridley
Brooke L
BL
Jenkins
Gregory D
GD
Batzler
Anthony
A
Suman
Vera J
VJ
Ravi
Saranya
S
Dixon
J Michael
JM
Miller
William R
WR
Wieben
Eric D
ED
Buzdar
Aman
A
Weinshilboum
Richard M
RM
Ingle
James N
JN
D000970:Antineoplastic Agents / Q000627:therapeutic use; D001141:Aromatase / Q000235:genetics*; D047072:Aromatase Inhibitors / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D024202:Electrophoretic Mobility Shift Assay; D004958:Estradiol / Q000097:blood; D005260:Female; D005838:Genotype; D006801:Humans; D020360:Neoadjuvant Therapy; D010641:Phenotype; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide
D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; D004958:Estradiol; D001141:Aromatase