Expression levels of uridine 5'-diphospho-glucuronosyltransferase genes in breast tissue from healthy women are associated with mammographic density

Abstract

IntroductionMammographic 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.MethodsGene 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.ResultsSAM-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.ConclusionsThree 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.

Lipid Metabolism Genes in Contralateral Unaffected Breast and Estrogen Receptor Status of Breast Cancer

“…UGT2B7 has unique specificity for 3,4-catechol estrogens and estriol, and may protect breast tissues from carcinogenic estrogen metabolites locally (43,44). Expression of UGT2B7 and 2B11 genes was found to be decreased in breast cancer and in benign biopsies from healthy women with high mammographic density, a strong breast cancer risk factor (45). DHRS2 (Hep27), a member of short-chain alcohol dehydrogenase/reductase (SDR) family of enzymes, has roles in ERþ breast cancer and is more frequently expressed in ERþ tumors (46).…”

Complexities of androgen receptor signalling in breast cancer

“…There is evidence that a variant allele ((TA) 7 /(TA) 7 ) of the UGT family member, UGT1A1, is associated with a reduced risk of ERa-negative breast cancer compared with ERa-positive breast cancer (Sparks et al 2004). In addition, reduced expression of UGT2B7, UGT2B10 and UGT2B11 is observed in highly dense normal breast tissues, an established breast cancer risk factor, compared with less-dense tissues (Haakensen et al 2010), suggesting that these enzymes can potentially contribute to breast tumourigenesis. However, whether or not changes in UGT affect breast tissue due to alterations in serum or tissue androgen or oestrogen levels is unknown.…”

Breast Density and Breast Cancer Risk: Understanding of Biology and Risk

“…Haakensen et al conducted gene expression profiling in biopsy material from 79 women without breast cancer and 64 women with breast cancer [48]. Among women without breast cancer, the biopsy was taken from an area with 'no visible pathology' but with some breast density.…”