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Tissue specific expression of extracellular microRNA in human breast cancers and normal human breast tissue in vivo.

ABSTRACT: Extracellular circulating microRNAs (miRNAs) have been suggested to be biomarkers for disease monitoring but data are inconsistent, one reason being that blood miRNA is of heterogeneous origin. Here, we sampled extracellular microRNAs locally in situ using microdialysis. Three different cohorts of women were included; postmenopausal women with ongoing breast cancer investigated within the cancer and in normal adjacent breast tissue, postmenopausal women investigated in their normal healthy breast and subcutaneous fat before and after six weeks of tamoxifen therapy, premenopausal women during the menstrual cycle. Samples were initially screened using TaqMan array cards with subsequently absolute quantification. 124 miRNA were expressed in microdialysates. After absolute quantifications extracellular miRNA-21 was found to be significantly increased in breast cancer. In addition, the levels were significantly higher in pre-menopausal breast tissue compared with postmenopausal. In breast tissue of pre-menopausal women miRNA-21 exhibited a cyclic variation during the menstrual cycle and in postmenopausal women six weeks of tamoxifen treatment decreased miRNA-21 suggesting that this miRNA may be important for breast carcinogenesis. None of these changes were found in plasma or microdialysates from subcutaneous fat. Our data revealed tissue specific changes of extracellular circulating miRNAs that would be otherwise unraveled using blood samples.

SUBMITTER: Abrahamsson A

PROVIDER: S-EPMC4673212 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Tissue specific expression of extracellular microRNA in human breast cancers and normal human breast tissue in vivo.

Abrahamsson Annelie A Dabrosin Charlotta C

Oncotarget 20150901 26

Extracellular circulating microRNAs (miRNAs) have been suggested to be biomarkers for disease monitoring but data are inconsistent, one reason being that blood miRNA is of heterogeneous origin. Here, we sampled extracellular microRNAs locally in situ using microdialysis. Three different cohorts of women were included; postmenopausal women with ongoing breast cancer investigated within the cancer and in normal adjacent breast tissue, postmenopausal women investigated in their normal healthy breas ...[more]

PMID: 26008976

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Project description:BackgroundBreast density and exposure to sex steroids are major risk factors for breast cancer. The local microenvironment plays an essential role in progression of breast cancer. Metabolic adaption is a major hallmark of cancer. Whether proteins from the extracellular space regulating metabolism are affected in breast cancer, dense breasts or by estrogen exposure are not yet fully elucidated.MethodsWomen with breast cancer, postmenopausal women with normal breast tissue with varying breast density or premenopausal women with breasts exposed to high levels of estradiol were included in the study. Microdialysis was used to collect proteins from the extracellular space in vivo in 73 women; 12 with breast cancer, 42 healthy postmenopausal women with different breast densities, and 19 healthy premenopausal women. Breast density was determined as lean tissue fraction (LTF) using magnetic resonance imaging. Data were evaluated in a murine breast cancer model. We quantified a panel of 92 key proteins regulating metabolism using proximity extension assay.ResultsWe report that 29 proteins were upregulated in human breast cancer. In dense breasts 37 proteins were upregulated and 17 of these were similarly regulated as in breast cancer. 32 proteins correlated with LTF. In premenopausal breasts 19 proteins were up-regulated and 9 down-regulated. Of these, 27 correlated to estradiol, a result that was confirmed for most proteins in experimental breast cancer. Only two proteins, pro-cathepsin H and galanin peptide, were similarly regulated in breast cancer, dense- and estrogen exposed breasts.ConclusionsMetabolic proteins may be targetable for breast cancer prevention. Depending on risk factor, this may, however, require different approaches as breast density and estradiol induce distinct different expression patterns in the breast. Additionally, metabolic proteins from the extracellular space may indeed be further explored as therapeutic targets for breast cancer treatment.

Project description:High serum levels of estradiol are associated with increased risk of postmenopausal breast cancer. Little is known about the gene expression in normal breast tissue in relation to levels of circulating serum estradiol.We compared whole genome expression data of breast tissue samples with serum hormone levels using data from 79 healthy women and 64 breast cancer patients. Significance analysis of microarrays (SAM) was used to identify differentially expressed genes and multivariate linear regression was used to identify independent associations.Six genes (SCGB3A1, RSPO1, TLN2, SLITRK4, DCLK1, PTGS1) were found differentially expressed according to serum estradiol levels (FDR = 0). Three of these independently predicted estradiol levels in a multivariate model, as SCGB3A1 (HIN1) and TLN2 were up-regulated and PTGS1 (COX1) was down-regulated in breast samples from women with high serum estradiol. Serum estradiol, but none of the differentially expressed genes were significantly associated with mammographic density, another strong breast cancer risk factor. In breast carcinomas, expression of GREB1 and AREG was associated with serum estradiol in all cancers and in the subgroup of estrogen receptor positive cases.We have identified genes associated with serum estradiol levels in normal breast tissue and in breast carcinomas. SCGB3A1 is a suggested tumor suppressor gene that inhibits cell growth and invasion and is methylated and down-regulated in many epithelial cancers. Our findings indicate this gene as an important inhibitor of breast cell proliferation in healthy women with high estradiol levels. In the breast, this gene is expressed in luminal cells only and is methylated in non-BRCA-related breast cancers. The possibility of a carcinogenic contribution of silencing of this gene for luminal, but not basal-like cancers should be further explored. PTGS1 induces prostaglandin E2 (PGE2) production which in turn stimulates aromatase expression and hence increases the local production of estradiol. This is the first report studying such associations in normal breast tissue in humans.

Project description:ObjectiveExposure to toxic metals such as mercury has been proposed to be a risk factor for the development of breast cancer since some metals can promote genetic mutations and epigenetic changes. We sought to find what toxic metals are present in normal breast tissue and in the tumours of women who had mastectomies for invasive ductal breast carcinoma.Materials and methodsFormalin-fixed paraffin-embedded blocks from mastectomies for breast carcinoma were examined from 50 women aged 34-69 years. Paraffin blocks selected for elemental analysis were from breast tissue not involved by carcinoma and from the carcinoma itself. Seven micrometer-thick sections were stained with autometallography to demonstrate the presence of mercury, and subjected to laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) to confirm the presence of mercury and to detect other toxic metals.ResultsAutometallography-detected mercury was seen in intraductal secretions and some luminal epithelial cells of normal breast lobules in 26 (55%) of the 47 samples where lobules were present, and in 10 (23%) of carcinomas from the 44 samples where carcinoma was present. In eight samples ductal carcinoma in situ was present and one of these contained mercury. LA-ICP-MS confirmed the presence of mercury in samples that stained with autometallography, and detected lead, iron, nickel, aluminium, chromium and cadmium in some samples.ConclusionsMercury was present in normal breast lobules in more than half of mastectomy samples that contained an invasive carcinoma, and in a smaller proportion of carcinomas and ductal carcinomas in situ. Other toxic metals that may interact synergistically with mercury could be detected in some samples. These findings do not provide direct evidence that toxic metals such as mercury play a role in the pathogenesis of breast cancer, but suggest that future molecular biological investigations on the role of toxic metals in breast cancer are warranted.

Dataset Information

Tissue specific expression of extracellular microRNA in human breast cancers and normal human breast tissue in vivo.

Publications

Tissue specific expression of extracellular microRNA in human breast cancers and normal human breast tissue in vivo.

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