Expression levels of uridine 5'-diphospho-glucuronosyltransferase genes in breast tissue from healthy women are associated with mammographic density.
BACKGROUND
Mammographic density (MD), as assessed from film screen mammograms, is determined by the relative content of adipose, connective and epithelial tissue in the female breast. In epidemiological studies, a high percentage of MD confers a four to six fold risk elevation of developing breast cancer, even after adjustment for other known breast cancer risk factors. However, the biologic correlates of density are little known.


METHODS
Gene expression analysis using whole genome arrays was performed on breast biopsies from 143 women; 79 women with no malignancy (healthy women) and 64 newly diagnosed breast cancer patients, both included from mammographic centres. Percent MD was determined using a previously validated, computerized method on scanned mammograms. Significance analysis of microarrays (SAM) was performed to identify genes influencing MD and a linear regression model was used to assess the independent contribution from different variables to MD.


RESULTS
SAM-analysis identified 24 genes differentially expressed between samples from breasts with high and low MD. These genes included three uridine 5'-diphospho-glucuronosyltransferase (UGT) genes and the oestrogen receptor gene (ESR1). These genes were down-regulated in samples with high MD compared to those with low MD. The UGT gene products, which are known to inactivate oestrogen metabolites, were also down-regulated in tumour samples compared to samples from healthy individuals. Several single nucleotide polymorphisms (SNPs) in the UGT genes associated with the expression of UGT and other genes in their vicinity were identified.


CONCLUSIONS
Three UGT enzymes were lower expressed both in breast tissue biopsies from healthy women with high MD and in biopsies from newly diagnosed breast cancers. The association was strongest amongst young women and women using hormonal therapy. UGT2B10 predicts MD independently of age, hormone therapy and parity. Our results indicate that down-regulation of UGT genes in women exposed to female sex hormones is associated with high MD and might increase the risk of breast cancer.
Haakensen
Vilde D
VD
Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Montebello, NO-0310, Norway.
Biong
Margarethe
M
Lingjærde
Ole Christian
OC
Holmen
Marit Muri
MM
Frantzen
Jan Ole
JO
Chen
Ying
Y
Navjord
Dina
D
Romundstad
Linda
L
Lüders
Torben
T
Bukholm
Ida K
IK
Solvang
Hiroko K
HK
Kristensen
Vessela N
VN
Ursin
Giske
G
Børresen-Dale
Anne-Lise
AL
Helland
Aslaug
A
D001706:Biopsy; D001940:Breast / Q000378:metabolism* / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D055106:Genome-Wide Association Study; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics; D016014:Linear Models; D008327:Mammography; D008875:Middle Aged; D010298:Parity; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D012307:Risk Factors
D007527:Isoenzymes; C552162:UGT2B10 protein, human; D014453:Glucuronosyltransferase
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