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Analysis of plasma small RNAs prior to breast cancer diagnosis

ABSTRACT: Overabundance of circulating RNY transcripts and fragments has been associated with cancer. Here we analyzed the levels of RNYs in plasma collected from women before developing breast cancer and compared the results to matched controls that remained unaffected. Using small RNA-seq, two cohorts were analyzed: a cohort of women carriers of pathogenic variants in BRCA1 and BRCA2, and diagnosed with breast cancer as a first neoplasm within a period of < 12 months after blood test (n = 11), or that provided a blood sample at a similar age and remained unaffected (n = 13); and a cohort from a long-term prospective study, and comprising 8 sporadic breast cancer cases (diagnosed in a period of < 12 months after blood test) and 8 controls matched for individual and epidemiological variables

ORGANISM(S): Homo sapiens

PROVIDER: GSE239907 | GEO | 2023/11/30

REPOSITORIES: GEO

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Project description:Five years of tamoxifen reduces breast cancer risk by nearly 50% but is associated with significant side-effects and toxicities. A better understanding of the direct and indirect effects of tamoxifen in benign breast tissue could elucidate new mechanisms of breast carcinogenesis, suggest novel chemoprevention targets, and provide relevant early response biomarkers for Phase II prevention trials. Seventy-three women at increased risk for breast cancer were randomized to tamoxifen (20 mg daily) or placebo for three months. Blood and breast tissue samples were collected at baseline and post-treatment. Sixty-nine women completed all study activities (37 tamoxifen and 32 placebo). The selected biomarkers focused on estradiol and IGFs in the blood, DNA methylation and cytology in random periareolar fine needle aspirates, and tissue morphometry, proliferation, apoptosis, and gene expression (microarray and RT-PCR) in the tissue core samples. Tamoxifen downregulated ets-oncogene family members ETV4 and ETV5 and reduced breast epithelial cell proliferation independent of CYP2D6 genotypes or effects on estradiol, ESR1 or IGFs. Reduction in proliferation was correlated with downregulation of ETV4 and DNAJC12. Tamoxifen also modulated expression of RAB GTPases, and several genes involved in epithelial-stromal interaction, and reduced tumor suppressor gene methylation. Three months of tamoxifen did not affect breast tissue composition, cytological atypia, preneoplasia or apoptosis. Tamoxifen may durably reduce breast cancer risk through downregulation of ETV4 and ETV5 which could deplete mammary progenitor populations. This pathway has the potential to provide novel targets and early response biomarkers for phase II prevention trials. Randomized prospective double blinded placebo-controlled trial of tamoxifen (20 mg daily) versus placeo in women at increased risk for breast cancer. Gene expression was assessed in whole breast tissue cores obtained at baseline and after three months of treatment for 35 women. Core biopsies were obtained in the late luteal phase (day 28 +/- 2) for premenopausal women (N = 19). Breast lobules from the baseline and post-treatment cores were microdissected for 5 tamoxifen subjects.

Project description:Introduction 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 generalized regression models were 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 among 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. Gene expression analysis of breast biopsies from 143 women, 79 non-cancer (healthy women with no cancer who had a mammogram taken) and 64 breast cancer.

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Analysis of plasma small RNAs prior to breast cancer diagnosis

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