| 1. |
- Busch, Susann, et al.
(författare)
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Loss of TGF beta Receptor Type 2 Expression Impairs Estrogen Response and Confers Tamoxifen Resistance
- 2015
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Ingår i: Cancer Research. - : American Association for Cancer Research. - 0008-5472 .- 1538-7445. ; 75:7, s. 1457-1469
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Tidskriftsartikel (refereegranskat)abstract
- One third of the patients with estrogen receptor alpha (ER alpha)-positive breast cancer who are treated with the antiestrogen tamoxifen will either not respond to initial therapy or will develop drug resistance. Endocrine response involves crosstalk between ER alpha and TGF beta signaling, such that tamoxifen non-responsiveness or resistance in breast cancer might involve aberrant TGF beta signaling. In this study, we analyzed TGF beta receptor type 2 (TGFBR2) expression and correlated it with ER alpha status and phosphorylation in a cohort of 564 patients who had been randomized to tamoxifen or no-adjuvant treatment for invasive breast carcinoma. We also evaluated an additional four independent genetic datasets in invasive breast cancer. In all the cohorts we analyzed, we documented an association of low TGFBR2 protein and mRNA expression with tamoxifen resistance. Functional investigations confirmed that cell cycle or apoptosis responses to estrogen or tamoxifen in ER alpha-positive breast cancer cells were impaired by TGFBR2 silencing, as was ER alpha phosphorylation, tamoxifen-induced transcriptional activation of TGF beta, and upregulation of the multidrug resistance protein ABCG2. Acquisition of low TGFBR2 expression as a contributing factor to endocrine resistance was validated prospectively in a tamoxifen-resistant cell line generated by long-term drug treatment. Collectively, our results established a central contribution of TGF beta signaling in endocrine resistance in breast cancer and offered evidence that TGFBR2 can serve as an independent biomarker to predict treatment outcomes in ER alpha-positive forms of this disease.
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| 2. |
- Liu, Yuwei, et al.
(författare)
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The effects of fermented rye products on gut microbiota and their association with metabolic factors in Chinese adults - an explorative study
- 2021
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Ingår i: Food and Function. - : Royal Society of Chemistry (RSC). - 2042-6496 .- 2042-650X. ; 12:19, s. 9141-9150
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Tidskriftsartikel (refereegranskat)abstract
- Rye is among the cereals with the highest content of dietary fibre. A high rye food intake has been associated with improved metabolic risk factors in some but not all observational and intervention studies. Whole-grain rye has also been suggested to affect the gut microbiota in individuals with metabolic syndrome. However, it is yet unclear to what extent effects on the gut microbiota mediate the beneficial metabolic responses of whole-grain rye intake. We hypothesized that a high intake of whole grain rye products containing fermented rye bran (FRB) vs. refined wheat based products (RW) could alter the gut microbiota and short-chain fatty acid (SCFA) composition towards a phenotype associated with beneficial metabolic effects in a population not used to such foods. For this purpose, we conducted a post hoc analysis of a 12-week randomized controlled trial in Chinese adults with Helicobacter pylori (HP) infection, with 53 participants consuming RW and 31 participants consuming FRB included in the analysis. Anthropometric measurements and fasting blood and fecal sample analyses as well as C-13-urea breath test were performed at baseline and after a 12-week intervention. At week 12, we observed a higher serum insulin concentration (P-value = 0.038) in the FRB group (n = 31) versus the RW group (n = 53), and this difference was corroborated with alterations in the genus-level relative abundances of the gut microbiota, represented by an increase in Romboutsia and a reduction in Bilophila in the FRB group (n = 22) versus the RW group (n = 46). Compared to the RW group (n = 53), fecal acetic acid concentration was significantly higher in the FRB group (n = 31) at week 12. We also found that fecal acetic and butyric acids positively, while isobutyric, isovaleric and 2-methylbutyric acids inversely, correlated with the gut Romboutsia level among all participants (n = 68) at week 12. We found positive correlations of fecal isobutyric, isovaleric and 2-methylbutyric acids with gut Bilophila (n = 68). In conclusion, our results suggest that the intake of high-fibre rye products could modify gut Romboutsia and Bilophila in a Chinese population with HP infection. These effects are paralleled with favorable modifications of the SCFA concentration and are associated with altered glycemic traits.
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| 3. |
- Tobin, Nicholas P., et al.
(författare)
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An Endothelial Gene Signature Score Predicts Poor Outcome in Patients with Endocrine-Treated, Low Genomic Grade Breast Tumors
- 2016
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Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 22:10, s. 2417-2426
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: The ability of vascular genes to provide treatment predictive information in breast cancer patients remains unclear. As such, we assessed the expression of genes representative of normal endothelial microvasculature (MV) in relation to treatment-specific patient subgroups. Experimental Design: We used expression data from 993 breast tumors to assess 57 MV genes (summarized to yield an MV score) as well as the genomic grade index (GGI) and PAM50 signatures. MV score was compared with CD31 staining by correlation and gene ontology (GO) analysis, along with clinicopathologic characteristics and PAM50 subtypes. Uni-, multivariate, and/or t-test analyses were performed in all and treatment-specific subgroups, along with a clinical trial cohort of patients with metastatic breast cancer, seven of whom received antiangiogenic therapy. Results: MV score did not correlate with microvessel density (correlation = 0.096), but displayed enrichment for angiogenic GO terms, and was lower in Luminal B tumors. In endocrine-treated patients, a high MV score was associated with decreased risk of metastasis [HR 0.58; 95% confidence interval (CI), 0.38-0.89], even after adjusting for histologic grade, but not GGI or PAM50. Subgroup analysis showed the prognostic strength of the MV score resided in low genomic grade tumors and MV score was significantly increased in metastatic breast tumors after treatment with sunitinib + docetaxel (P = 0.031). Conclusions: MV score identifies two groups of better and worse survival in low-risk endocrine-treated breast cancer patients. We also show normalization of tumor vasculature on a transcriptional level in response to an angiogenic inhibitor in human breast cancer samples.
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