Predicting immune responsiveness in ER-positive breast cancer
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE298750 | GEO | 2025/07/30
REPOSITORIES: GEO
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Project description:Predicting immune responsiveness in ER-positive breast cancer
| PRJNA1271078 | ENA
Project description:We performed single cell RNA sequencing (RNA-seq) for 549 primary breast cancer cells and lymph node metastases from 11 patients with distinct molecular subtypes (BC01-BC02, estrogen receptor positive (ER+); BC03, double positive (ER+ and HER2+); BC03LN, lymph node metastasis of BC03; BC04-BC06, human epidermal growth factor receptor 2 positive (HER2+); BC07-BC11, triple-negative breast cancer (TNBC); BC07LN, lymph node metastasis of BC07) and matched bulk tumors. We separated these single cells into epithelial tumor and tumor-infiltrating immune cells using inferred CNVs from RNA-seq. The refined single cell profiles for the tumor and immune cells provide key expression signatures of breast cancer and the surrounding microenvironment.
2016-12-09 | GSE75688 | GEO
Project description:The lymphatic system is a common avenue for the spread of breast cancer cells and dissemination through it occurs at least as frequently as hematogenous metastasis. Approximately 75% of primary breast cancers are estrogen receptor (ER) positive and the majority of these maintain receptor expression as lymph node (LN) metastases. However, it is unknown if ER function is equivalent in cancer cells growing in the breast and in the LNs. We have developed a model to assess estrogen responsiveness in ER(+) breast tumors and LN metastases. Fluorescent ER(+) MCF-7 tumors were grown in ovariectomized nude mice supplemented with estradiol. Once axillary LN metastasis arose, estradiol was withdrawn (EWD), for 1 or 4 weeks, or continued, to assess estradiol responsiveness. On EWD, proliferation rates fell similarly in tumors and LN metastases. However, estradiol-dependent ER down-regulation and progesterone receptor induction were deficient in LN metastases, indicating that ER-dependent transcriptional function was altered in the LN. Cancer cells from estradiol-treated and EWD primary tumors and matched LN metastases were isolated by laser capture microdissection. Global gene expression profiling identified transcripts that were regulated by the tissue microenvironment, by hormones, or by both. Interestingly, numerous genes that were estradiol regulated in tumors lost estradiol sensitivity or were regulated in the opposite direction by estradiol in LN metastases. We propose that the LN microenvironment alters estradiol signaling and may contribute to local antiestrogen resistance. Keywords: Breast cancer lymph node metastasis, ER positive, MCF7, xenograft
2008-05-02 | GSE11317 | GEO
Project description:The lymphatic system is a common avenue for the spread of breast cancer cells and dissemination through it occurs at least as frequently as hematogenous metastasis. Approximately 75% of primary breast cancers are estrogen receptor (ER) positive and the majority of these maintain receptor expression as lymph node (LN) metastases. However, it is unknown if ER function is equivalent in cancer cells growing in the breast and in the LNs. We have developed a model to assess estrogen responsiveness in ER(+) breast tumors and LN metastases. Fluorescent ER(+) MCF-7 tumors were grown in ovariectomized nude mice supplemented with estradiol. Once axillary LN metastasis arose, estradiol was withdrawn (EWD), for 1 or 4 weeks, or continued, to assess estradiol responsiveness. On EWD, proliferation rates fell similarly in tumors and LN metastases. However, estradiol-dependent ER down-regulation and progesterone receptor induction were deficient in LN metastases, indicating that ER-dependent transcriptional function was altered in the LN. Cancer cells from estradiol-treated and EWD primary tumors and matched LN metastases were isolated by laser capture microdissection. Global gene expression profiling identified transcripts that were regulated by the tissue microenvironment, by hormones, or by both. Interestingly, numerous genes that were estradiol regulated in tumors lost estradiol sensitivity or were regulated in the opposite direction by estradiol in LN metastases. We propose that the LN microenvironment alters estradiol signaling and may contribute to local antiestrogen resistance. Experiment Overall Design: 10 samples, including 3 each of estrogen and estrogen withdrawn axillary lymph nodes and 2 each of estrogen and estrogen withdrawn primary mammary gland tumors.
2008-06-11 | E-GEOD-11317 | biostudies-arrayexpress
Project description:Organoid cultures offer a powerful technology to investigate many different aspects of development, physiology, and pathology of diverse tissues. Unlike standard tissue culture of primary breast epithelial cells, breast organoids preserve the epithelial lineages and architecture of the normal tissue. However, existing organoid culture methods are tedious, difficult to scale, and do not robustly retain estrogen receptor (ER) expression and responsiveness in long-term culture. Here, we describe a modified culture method to generate and maintain organoids as suspension cultures. This method improves organoid growth and uniformity over the traditional Matrigel dome embedding method while still maintaining the fidelity of the three major epithelial lineages. Using this adopted method, we are able to isolate and culture hormone sensing (HS) cells alone that retain ER responsiveness upon estrogen stimulation in long-term culture. This culture system presents a valuable opportunity to study the events involved in initiation and evolution of ER-positive breast cancer.
2024-12-27 | GSE266935 | GEO
Project description:To better understand the biology of hormone receptor-positive and negative breast cancer and to identify methylated gene markers of disease progression, we performed a genome-wide methylation array analysis on 103 primary invasive breast cancers and 21 normal breast samples using the Illumina Infinium HumanMethylation27 array that queried 27,578 CpG loci. Estrogen and/or progesterone receptor-positive tumors displayed more hypermethylated loci than ER-negative tumors. However, the hypermethylated loci in ER-negative tumors were clustered closer to the transcriptional start site compared to ER-positive tumors. An ER-classifier set of CpG loci was identified, which independently partitioned primary tumors into ER-subtypes. Forty (32 novel, 8 previously known) CpG loci showed differential methylation specific to either ER-positive or ER-negative tumors. Each of the 40 ER-subtype-specific loci was validated in silico using an independent, publicly available methylome dataset from The Cancer Genome Atlas (TCGA). In addition, we identified 100 methylated CpG loci that were significantly associated with disease progression; the majority of these loci were informative particularly in ER-negative breast cancer. Overall, the set was highly enriched in homeobox containing genes. This pilot study demonstrates the robustness of the breast cancer methylome and illustrates its potential to stratify and reveal biological differences between ER-subtypes of breast cancer. Further, it defines candidate ER-specific markers and identifies potential markers predictive of outcome within ER subgroups. Frozen breast cancer tissues that were excised from patients with Stage 1-3 disease prior to treatment (n=103) were retrieved from Surgical Pathology at Johns Hopkins Hospital (Baltimore, Maryland) and confirmed to contain > 50% epithelial cells. Normal breast organoids were prepared by enzymatic digestion of reduction mammoplasty specimens (n=15; median patient age = 52 years, range 47 to 71). Normal ducts from breast tissue > 2 cm away from the tumor (n=6) were isolated from cryosections using laser-capture micro-dissection (PALM MicroBeam, Carl Zeiss Microimaging, North America). To determine the differences in breast cancer biology/behavior between ER subtypes, we characterized methylation patterns at 8376 selected CpG loci according to ER status. These loci met two criteria: 1) showed the most variation across primary tumors (SD >0.100) and 2) had probe detection p-values <0.0001. To develop an epigenomic signature that predicts outcome in patients with breast cancer, we conducted differential methylation analysis on primary tumors from recurrent versus non-recurrent breast cancers. We used a subgroup of 82 well-annotated, invasive breast tumors derived from the discovery set of 103 tumors that included 44 ER-positive (7 recurrences) and 38 ER-negative (11 recurrences) breast cancers and independently queried the ER-positive and ER-negative tumor groups
2011-09-08 | E-GEOD-31979 | biostudies-arrayexpress
Project description:Chronic inflammation promotes breast tumor growth and invasion by accelerating angiogenesis and tissue remodeling in the tumor microenvironment. The relationship between inflammation and estrogen, which drives the growth of 70 percent of breast tumors, is complex. Low levels of estrogen exposure stimulate macrophages and other inflammatory cell populations, but very high levels are immune suppressive. Breast tumor incidence is increased by obesity and age, which interact to influence inflammatory cell populations in normal breast tissue. The molecular impact of these factors on tumor initiation and growth is not well-understood. We modeled the difference in gene expression between 195 breast adenocarcinomas and 195 matched adjacent normal breast tissue samples, using age, body mass index (BMI), and tumor subtype as covariates. Age and BMI were independently associated with inflammation in normal tissue but not tumors. Older patients with ER-positive disease had tumors with higher levels of Estrogen Receptor (ER) signaling compared to adjacent normal tissue and had lower relative levels of tumor macrophage expression. We developed a novel statistic to quantify the rewiring of gene co-expression networks and demonstrate that in ER-positive tumors basal gene networks are rewired even though their expression levels of these genes are not significantly different from those in adjacent normal tissue. Patient age influences the molecular profile of ER-positive breast tumors. Our data support an immunosuppressive effect of estrogen signaling in the breast tumor microenvironment, suggesting this effect contributes to the greater presence of prognostic and therapeutically relevant immune cells in ER-negative tumors. 137 total samples: 43 mammaplastic reduction, 47 breast adenocarcinoma, 47 paired adjacent normal breast tissue
2016-07-01 | E-GEOD-70905 | biostudies-arrayexpress
Project description:Chronic inflammation promotes breast tumor growth and invasion by accelerating angiogenesis and tissue remodeling in the tumor microenvironment. The relationship between inflammation and estrogen, which drives the growth of 70 percent of breast tumors, is complex. Low levels of estrogen exposure stimulate macrophages and other inflammatory cell populations, but very high levels are immune suppressive. Breast tumor incidence is increased by obesity and age, which interact to influence inflammatory cell populations in normal breast tissue. The molecular impact of these factors on tumor initiation and growth is not well-understood. We modeled the difference in gene expression between 195 breast adenocarcinomas and 195 matched adjacent normal breast tissue samples, using age, body mass index (BMI), and tumor subtype as covariates. Age and BMI were independently associated with inflammation in normal tissue but not tumors. Older patients with ER-positive disease had tumors with higher levels of Estrogen Receptor (ER) signaling compared to adjacent normal tissue and had lower relative levels of tumor macrophage expression. We developed a novel statistic to quantify the rewiring of gene co-expression networks and demonstrate that in ER-positive tumors basal gene networks are rewired even though their expression levels of these genes are not significantly different from those in adjacent normal tissue. Patient age influences the molecular profile of ER-positive breast tumors. Our data support an immunosuppressive effect of estrogen signaling in the breast tumor microenvironment, suggesting this effect contributes to the greater presence of prognostic and therapeutically relevant immune cells in ER-negative tumors. 296 total samples: 148 breast adenocarcinoma, 148 paired adjacent normal breast tissue
2016-07-01 | E-GEOD-70947 | biostudies-arrayexpress
Project description:Breast cancer is a heterogeneous disease comprised of at least five major subtypes. Luminal subtype tumors confer a more favourable patient prognosis, which is in part, attributed to the Estrogen Receptor-alpha (ER) positivity and anti-hormone responsiveness of these tumors. Expression of the forkhead box transcription factor, FOXA1, also correlates with the luminal subtype and patient survival, but is present in a subset of ER-negative tumors. Similarly, FOXA1 is consistently expressed in luminal breast cancer cell lines even in the absence of ER. In contrast, basal breast cancer cell lines do not express FOXA1, and loss of FOXA1 in luminal cells increases migration and invasion, characteristics of the basal subtype. To delineate an ER-independent role for FOXA1 in maintaining the luminal phenotype, and hence a more favourable prognosis, we performed cDNA microarray analyses on luminal FOXA1-positive, ER-positive (MCF7, T47D) and FOXA1-positive, ER-negative (MDA-MB-453, SKBR3) cell lines in the presence or absence of transient FOXA1 silencing. This resulted in three FOXA1 transcriptomes: (1) a luminal-signature (consistent across cell lines), (2) an ER-positive signature (restricted to MCF7 and T47D) and (3) an ER-negative signature (restricted to MDA-MB-453 and SKBR3). Use of Gene Set Enrichment Analyses (GSEA) as a phenotyping tool revealed that FOXA1 silencing resulted in a transcriptome shift from luminal to basal gene expression signatures. FOXA1 binds to both luminal and basal genes within luminal breast cancer cells, suggesting that it not only transactivates luminal genes, but also represses basal-associated genes. From these results we conclude that FOXA1 controls plasticity between basal and luminal cells, playing a dominant role in repressing the basal phenotype, and thus tumor aggressiveness, in luminal breast cancer cells. Although it has been proposed that FOXA1-targeting agents may be useful for treating luminal tumors, these data suggest that this approach may promote transitions toward a more aggressive cancer. FOXA1 siRNA treated breast cell lines compared directly to nonspecific siRNA treated cell lines using Agilent 4X44 microarrays.
2012-03-09 | E-GEOD-31003 | biostudies-arrayexpress
Project description:Estrogen receptor (ER) signaling–dependent cancer cell growth is one of the major features of ER-positive breast cancer (BC). Inhibition of ER function is a standard and effective treatment for ER-positive tumors; however, ~20% of patients with ER-positive BC experience early or late recurrence. In this study, we examined intertumor heterogeneity from an epigenetic perspective based on the hypothesis that the intrinsic difference in epigenetic states around ER signaling pathway underlies endocrine therapy resistance. We profiled chromatin accessibility data from 42 BC samples, including 35 ER-positive human epidermal growth factor receptor 2 (HER2)-negative and 7 triple-negative tumors, identifying a subgroup of ER-positive BCs with a distinctive chromatin accessibility pattern including reduced accessibility to ER-responsive elements (EREs). The same subgroup was also observed in The Cancer Genome Atlas BC cohort. Despite the reduced accessibility to EREs, the expression of ER and potential ER target genes were not decreased in these tumors. Our findings highlight the existence of a subset of ER-positive BCs with unchanged ER expression but reduced EREs accessibility that cannot be distinguished by conventional immunostaining for ER. Future studies should determine whether these tumors are associated with resistance to endocrine therapy.
2023-01-09 | GSE222116 | GEO