Breast cancer microbiota in hormonal receptor positive patients
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PROVIDER: PRJEB76812 | ENA |
REPOSITORIES: ENA
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Project description:Background: Estrogen receptor positive (ER+) breast cancers (BC) are heterogeneous with regard to their clinical behavior and response to therapies. The ER is currently the best predictor of response to the anti-estrogen agent tamoxifen, yet up to 30-40% of ER+BC will relapse despite tamoxifen treatment. New prognostic biomarkers and further biological understanding of tamoxifen resistance are required. We used gene expression profiling to develop an outcome-based predictor using a training set of 255 ER+ BC samples from women treated with adjuvant tamoxifen monotherapy. We used clusters of highly correlated genes to develop our predictor to facilitate both signature stability and biological interpretation. Independent validation was performed using 362 tamoxifen-treated ER+ BC samples obtained from multiple institutions and treated with tamoxifen only in the adjuvant and metastatic settings. Results: We developed a gene classifier consisting of 181 genes belonging to 13 biological clusters. In the independent set of adjuvantly-treated samples, it was able to define two distinct prognostic groups (HR 2.01 95%CI: 1.29-3.13; p=0.002). Six of the 13 gene clusters represented pathways involved in cell cycle and proliferation. In 112 metastatic breast cancer patients treated with tamoxifen, one of the classifier components suggesting a cellular inflammatory mechanism was significantly predictive of response. Conclusions: We have developed a gene classifier that can predict clinical outcome in tamoxifen-treated ER+ BC patients. Whilst our study emphasizes the important role of proliferation genes in prognosis, our approach proposes other genes and pathways that may elucidate further mechanisms that influence clinical outcome and prediction of response to tamoxifen. Keywords: disease state analysis
2008-05-07 | GSE9195 | GEO
Project description:PurposeTo investigate predictors of treatment interruption and early discontinuation of adjuvant hormonal therapy (HT) in a retrospective cohort of women with newly diagnosed hormone receptor-positive (HR +) breast cancer.MethodsEligible cases were identified from a single institutional tumor registry from 2009 to 2015. Patients were followed from initiation of adjuvant HT for a minimum of one year through December 1, 2016. Predictors of treatment interruption or early discontinuation were analyzed with Cox proportional hazards regression models.ResultsWith a median follow-up time of 3.0 years (IQR 1.5-4.5), 22 women (10.9%) discontinued HT early and 47 (23.4%) had at least one treatment interruption of > 14 days. Adjusted Cox proportional hazards regression models showed that women with pre-existing affective disorders were more likely to discontinue therapy early (HR 3.15; 95% CI 1.35-7.37), while those with pre-existing chronic pain disorders were at increased risk for treatment interruption (HR 2.24; 95% CI 1.20-4.19). HT-related symptoms were the most commonly reported reason for HT interruption or discontinuation. Women who experienced severe treatment-related symptoms were at increased risk for both HT interruption (HR 2.64; 95% CI 1.07-6.50) and HT discontinuation (HR 3.48; 95% CI 1.20-10.1).ConclusionsThis study showed that HT interruptions and discontinuation were common, often associated with HT-related symptoms. Clinicians caring for breast cancer patients on HT should monitor closely for treatment-emergent symptoms, especially women with pre-existing disorders, and support them to continue therapy through aggressive symptom management and other patient-centered approaches.
| S-EPMC11372730 | biostudies-literature
Project description:Resistance to CDK4/6 inhibitors leads to treatment failure and disease progression in women with HR+HER2- breast cancer (BC). We delineated a hypoxia-sensitive, CCL2-dependent pathway recruiting IL17A-secreting γδ T cells to mouse HR+HER2- BCs upon CDK4/6 inhibition, resulting in repolarization of tumor-associated macrophages (TAMs) towards an immunosuppressive CX3CR1+ phenotype associated with resistance. Increased IL17A signaling and intratumoral γδ T cell abundance positively correlated with advanced grade and/or reduced survival in two cohorts of HR+HER2- BC patients. Circulating γδ T cells and plasma CCL2 levels negatively correlated with progression in an independent series of patients with HR+HER2- BC receiving CDK4/6 inhibitors. Intratumoral γδ T cells were increased in post- vs pre-treatment biopsies from HR+HER2- BC patients relapsing on CDK4/6 inhibitors. CX3CR1+ TAMs had negative prognostic impact in women with HR+HER2- BC receiving neoadjuvant PD-1 blockage and radiotherapy. Thus, γδ T cells and CX3XR1+ TAMs may favor resistance to CDK4/6 inhibitors in HR+HER2- BC patients.
2025-05-09 | GSE296805 | GEO
Project description:Resistance to CDK4/6 inhibitors leads to treatment failure and disease progression in women with HR+HER2- breast cancer (BC). We delineated a hypoxia-sensitive, CCL2-dependent pathway recruiting IL17A-secreting γδ T cells to mouse HR+HER2- BCs upon CDK4/6 inhibition, resulting in repolarization of tumor-associated macrophages (TAMs) towards an immunosuppressive CX3CR1+ phenotype associated with resistance. Increased IL17A signaling and intratumoral γδ T cell abundance positively correlated with advanced grade and/or reduced survival in two cohorts of HR+HER2- BC patients. Circulating γδ T cells and plasma CCL2 levels negatively correlated with progression in an independent series of patients with HR+HER2- BC receiving CDK4/6 inhibitors. Intratumoral γδ T cells were increased in post- vs pre-treatment biopsies from HR+HER2- BC patients relapsing on CDK4/6 inhibitors. CX3CR1+ TAMs had negative prognostic impact in women with HR+HER2- BC receiving neoadjuvant PD-1 blockage and radiotherapy. Thus, γδ T cells and CX3XR1+ TAMs may favor resistance to CDK4/6 inhibitors in HR+HER2- BC patients.
2025-05-09 | GSE296798 | GEO
Project description:Breast cancer (BC) is the most prevailing type of cancer among women in the world. ERα protein, which is transcribed and translated by estrogen receptor gene ESR1, is one of the marker molecules for clinical classification of BC. However, whether circRNAs specifically expressed in hormone receptor-positive BC play a role which is independent of ERα (estrogen receptor alpha) protein activity and signaling pathways is unknown. Whether these circRNAs could impinge on the sensitivity of ER+ BC cells to the endocrine therapy and targeted drug therapy is also unexplored.By screening circRNAs involved in estrogen receptor (ER) signaling, circESR1 was identified as a circRNA exhibiting high specificity of expression in ER+ breast cancer. Our studies elucidate a novel signaling complex centering around circESR1 and HNRNPAB in ER+ breast cancer and suggest that circESR1 might represent a potential therapeutic target for this disease.
2025-06-17 | GSE286447 | GEO
Project description:Estrogen receptor α (ER-α) is a major driver of breast cancer (BC), being expressed in 75% of all BC cases. Agents such as tamoxifen are used to block ER-α activity and interfere with its down-stream oncogenic singling. However, a major problem associated with tamoxifen is the emergence of resistance. Resistant BC is often associated with aggressive relapse, metastasis, and high mortality rates of 80%. A key mechanism for development of resistance is activation of EGFR/HER2/HER3 signaling pathways and other hormone receptors (androgen receptor (AR), progesterone receptor (PR), prolactin receptors (PRL-R)) that can intrinsically activate ER-α. This study investigated a novel class of thiosemicarbazone anti-cancer agents, namely Dp44mT and DpC, on the expression and activation between major BC hormonal receptors, their co-factors and key pathways involved in resistance in ER-α-positive BC using RNA sequencing, immunoblotting and confocal microscopy and an in vivo orthotopic BC model. For the first time, we demonstrate that DpC and Dp44mT markedly reduce the expression of ER-α, AR, PR and PRL-R by inducing their proteasomal degradation. Further, these agents also inhibited EGFR, HER2 and HER3 activation in ER-α-positive BC cells, suggesting their potential ability to overcome development of resistance. Importantly, expression of key co-factors that promote ER-α-transcriptional activity, including SRC3, c-Myc, SP1, and c-Src, were also decreased by these agents. This study demonstrates for the first time the multi-axial inhibitory effects of the novel DpT agents in ER-positive BC invitro and in vivo. We demonstrate that Dp44mT and DpC decrease ER-α expression, transcriptional activity, and promote its proteasomal degradation. This study also demonstrated the ability of the DpT agents in inhibiting RTKs and key oncogenic pathways that are well established to promote endocrine resistance. Hence, for the first time we demonstrate that Dp44mT and DpC may be a promising therapeutic approach to treat ER-positive BC and to overcome resistance to conventional BC therapies.
2023-02-28 | GSE192942 | GEO
Project description:Estrogen receptor α-positive (ER+) breast cancers (BCs) represent more than 70% of all breast cancers and pose a particular clinical challenge because they recur up to decades after initial diagnosis and treatment. The mechanisms governing tumor cell dormancy and latent disease remain elusive due to a lack of adequate models. Here, we compare tumor progression of ER+ and triple-negative (TN) BC subtypes with a clinically relevant mouse intraductal xenografting approach (MIND). Both ER+ and TN BC cells disseminate already during the in situ stage. However, TN disseminated tumor cells (DTCs) proliferate at the same rate as cells at the primary site and give rise to macro-metastases. ER+ DTCs have low proliferative indices, form only micro-metastases and lose epithelial characteristics. Single cell RNA sequencing reveals that dormant DTCs harbor different Epithelial-Mesenchymal Plasticity (EMP)-states, reflective of their heterogeneous and plastic nature. Dormant DTCs are in a mesenchymal-like state, with decreased CDH1 and increased ZEB2 and VIM expression levels, as well as matrisome-related genes, like FN1, ELN, COL3A1, and others. On the other hand, proliferative DTCs are epithelial-like, and express CDH1, EPCAM, KRT18, and ESR1. EMP is very rare in primary tumour cells and is not required for invasion or metastasis. In vivo, forced transition to the epithelial state through ectopic E-cadherin expression overcomes dormancy with increased growth of lung metastases. We conclude that EMP is essential for the generation of a dormant cell state and the development of latent disease. Targeting exit from EMP is of therapeutic potential.
2022-07-13 | GSE196936 | GEO
Project description:Background: Numerous studies have focused on the PI3K/AKT/mTOR pathway in estrogen receptor positive (ER) breast cancer (BC), as a linear signal transduction pathway and reported its association with worse clinical outcomes. To gain better insight into the relative contribution of each of the signalling pathways which lie downstream to PI3K (namely AKT and mTOR) to BC outcomes, we have developed a novel in silico approach which assessed the activation of each of these signalling pathways separately. Methods: By analysing gene expression and matched proteomic data in ER-positive patients from the TCGA repository, we developed gene signatures that reflect the level of expression of phosphorylated-Serine473-AKT (pAKT) and phosphorylated-Serine2448-mTOR (p-mTOR) separately, capturing their corresponding level of pathway activation. Using pooled analysis of gene-expression data from over 7,000 patients with ER-positive early BC, we then investigated the association between pathway activation and outcomes. Results: Our analysis revealed that the pAKT pathway activation (as measured by the developed signature) was associated with luminal A BC while the p-mTOR pathway activation was more associated with luminal B BC (Kruskal-Wallis test p<10-10). pAKT pathway activation was significantly associated with better outcomes (multivariable HR, 0.79; 95% CI, 0.74 to 0.85; p=2.5x10-10) whereas p-mTOR pathway activation showed worse outcomes (multivariable HR, 1.1; 95% CI, 1.1 to 1.2; p=9.9x10-4). Similar associations between activation and outcomes were obtained when the analysis was performed in patients who were treated with hormonal therapy. Additionally, pAKT pathway activation predicted better outcomes irrespective of the BC molecular subtypes (luminal A multivariable HR, 0.85; 95% CI, 0.75 to 0.96; p=0.01; luminal B HR, 0.91; 95% CI, 0.83 to 0.99; p=0.033). pAKT pathway activation was associated with PIK3CA mutations (p=0.0001) while p-mTOR pathway activation was associated with p53 mutations (p=0.04). Finally, we show that pAKT pathway activation was associated with less response to Everolimus. Conclusions: Our data show that pAKT and p-mTOR pathway activation have differing impact on prognosis and suggest that they are not linearly connected in luminal breast cancers. These findings add to our understanding of signalling through the PI3K pathway and could have important implications for the treatment of luminal BC.
2018-12-14 | GSE123831 | GEO
Project description:Inflammation affects tumor immune surveillance and resistance to therapy. Here we show that production of interleukin (IL)-1b in primary breast cancer (BC) tumors is linked with advanced disease. Patients with metastatic HER2-negative BC display a transcriptional signature of inflammation in the blood, which is attenuated after IL1 blockade.
2018-08-21 | GSE118646 | GEO
Project description:Breast cancer (BC) is the most prevailing type of cancer among women in the world. HNRNPAB belongs to heterogeneous nuclear ribonucleoproteins (hnRNPs) subfamily.In recent years, studies have found that HNRNPAB can be involved in the progression of various human cancers. It not only combines with DNA and RNA, but also mediates mRNA nuclear transport, regulates gene transcription and translation, and regulates the proliferation, migration, invasion, aging, and other phenotypes of tumor cells. HNRNPAB is closely related to the poor prognosis of cancer patients. In addition, HNRNPAB is also involved in regulating the infection process of influenza virus. It has been simply reported that the relevance of HNRNPAB as a prognostic value in BC.
2025-06-17 | GSE286448 | GEO