Discordant cellular response to pre-surgical letrozole in bilateral synchronous ER+ breast cancers with a KRAS mutation or FGFR1 gene amplification
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ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Justin Balko
PROVIDER: E-GEOD-39387 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:This clinical case resulted from an ongoing trial at Vanderbilt University and abroad where ER+ breast cancer patients are administered 2-3 weeks of aromatase inhibitor therapy leading up to definitive surgical resection of the tumor. In this case, we describe a study patient presenting with bilateral primary ER+ breast tumors. Short term hormonal therapy substantially reduced proliferation in one tumor, while the second was essentially unchanged. Extensive molecular and genetic workup of the two tumors yielded divergent lesions in the two tumors; an activating KRAS mutation in the responsive tumor, and an amplification of the FGFR1 locus in the treatment-refractory tumor.
2012-07-17 | GSE39387 | GEO
Project description:RNA-seq was performed on breast cancer cell lines and primary tumors RNA-seq was performed on 28 breast cancer cell lines, 42 Triple Negative Breast Cancer (TNBC) primary tumors, and 42 Estrogen Receptor Positive (ER+) and HER2 Negative Breast Cancer primary tumors, 30 uninovlved breast tissue samples that were adjacent to ER+ primary tumors, 5 breast tissue samples from reduction mammoplasty procedures performed on patients with no known cancer, and 21 uninvolved breast tissue samples that were adjacent to TNBC primary tumors.
2014-06-11 | E-GEOD-58135 | biostudies-arrayexpress
Project description:Endoplasmic reticulum (ER) stress triggers an adaptive response which fosters tumor cell survival and resilience to stress conditions. Activation of the endoplasmic reticulum stress response, through its PERK branch, promotes the phosphorylation of the α-subunit of translation initiation factor eIF2alpha, thereby repressing general protein translation and selectively augmenting the translation of ATF4 with the downstream CHOP transcription factor and the protein disulfide oxidase ERO1. Here, we show that ISRIB, a small molecule, which inhibits the action of the phosphorylated α-subunit of eIF2, thereby activating protein translation, synergistically interacts with the genetic deficiency of protein disulfide oxidase ERO1 enfeebling tumor growth and spreading. ISRIB represses CHOP signal but surprisingly does not inhibit ERO1. Mechanistically, ISRIB increases the ER protein load with a prominent perturbing effect on ERO1 deficient Triple-Negative breast cells, which have adapted to live with low client protein load, while ERO1 deficiency selectively impairs VEGF-dependent angiogenesis. Strikingly, ERO1-deficient Triple Negative Breast Cancer xenografts have augmented ER stress response and PERK branch. In vivo, ISRIB synergistically with ERO1 deficiency inhibits the growth of Triple-Negative Breast cancer xenografts by impairing proliferation and angiogenesis, while it is not effective on the xenograft counterparts with ERO1. In summary, these results demonstrate that ISRIB together with ERO1 deficiency synergistically shatters a feature of the adaptive ER stress response while ERO1 deficiency selectively impairs angiogenesis in tumors, thereby together promoting tumor cytotoxicity. Therefore, our findings suggest two surprising findings in breast tumors: ERO1 is not regulated via CHOP and ISRIB represents a therapeutic option to efficiently inhibit tumor progression in those tumors with limited ERO1 and high PERK.
2022-07-20 | E-MTAB-11313 | biostudies-arrayexpress
Project description:Limited knowledge of the changes in estrogen receptor (ER) signaling during the transformation of the normal mammary gland to breast cancer hinders the development of effective prevention and treatment strategies. Differences in estrogen signaling between normal human primary breast epithelial cells and primary breast tumors obtained immediately following surgical excision were explored. Transcriptional profiling of normal ER+ mature luminal mammary epithelial cells and ER+ breast tumors revealed significant difference in the response to estrogen stimulation. Consistent with these differences in gene expression, the normal and tumor ER cistromes were distinct and sufficient to segregate normal breast tissues from breast tumors. The selective enrichment of the DNA binding motif GRHL2 in the breast cancer-specific ER cistrome suggests that it may play a role in the differential function of ER in breast cancer. Depletion of GRHL2 resulted in altered ER binding and differential transcriptional responses to estrogen stimulation. Furthermore, GRHL2 was demonstrated to be essential for estrogen-stimulated proliferation of ER+ breast cancer cells. DLC1 was also identified as an estrogen-induced tumor suppressor in the normal mammary gland with decreased expression in breast cancer. In clinical cohorts, loss of DLC1 and gain of GRHL2 expression are associated with breast cancer and are independently predictive for worse survival. This study suggests that normal ER signaling is lost and tumor-specific ER signaling is gained during breast tumorigenesis. Unraveling these changes in ER signaling during breast cancer progression should aid the development of more effective prevention strategies and targeted therapeutics. SIGNIFICANCE STATEMENT: Abnormal estrogen receptor (ER) signaling drives the majority of breast cancers and is targeted by endocrine therapies. However, in normal breast tissue, ER signaling has been demonstrated to promote benign functions such as development and differentiation. Using genomic techniques to characterize ER function in normal breast and breast tumors, this study reveals differential patterns of ER signaling, suggesting that normal ER signaling is lost and tumorigenic ER signaling gained during breast tumor formation. Better understanding of this process can aid the development of improved breast cancer prevention strategies and therapies.
2019-05-27 | GSE99680 | GEO
Project description:Using microarray-based technology, we have performed a microRNA expression analysis in 75 primary breast tumors from patients that either remained disease-free at 5 years post-surgery (group A) or developed early (group B) or late (group C) recurrence after surgical removal of the tumor and we have have identified a set of recurrence-related microRNAs with potential prognostic value to identify patients who will likely develop metastasis early after primary breast surgery.
2013-10-16 | E-MTAB-1989 | biostudies-arrayexpress
Project description:We aimed to find clinically relevant gene activities ruled by the signal transducer and activator of transcription 3 (STAT3) proteins in an ER(-) breast cancer population via network approach. STAT3 is negatively associated with both lymph nodal category and stage. MYC is a component of STAT3 network. MYC and STAT3 may co-regulate gene expressions for Warburg effect, stem cell like phenotype, cell proliferation and angiogenesis. We identified a STAT3 network in silico showing its ability in predicting its target gene expressions primarily for specific tumor subtype, tumor progression, treatment options and prognostic features. The aberrant expressions of MYC and STAT3 are enriched in triple negatives (TN). They promote histological grade, vascularity, metastasis and tumor anti-apoptotic activities. VEGFA, STAT3, FOXM1 and METAP2 are druggable targets. High levels of METAP2, MMP7, IGF2 and IGF2R are unfavorable prognostic factors. STAT3 is an inferred center regulator at early cancer development predominantly in TN. 91 specimens of primary infiltrating ductal carcinoma of breast (IDC) included triple negatives(48/91), ERBB2+(29/91),ER(-)PR(+)HER(-)(5/91), ER(-)PR(+)HER(+)(6/91) and ER(-) but HER(?)(3/91). Five specimens for metaplastic carcinoma of breast (MCB) were included. Seven non-tumor samples were surgically taken from breast tissue adjacent to some of 91 ER(-) IDC breast tumors as a control in this study.
2012-09-25 | E-GEOD-32641 | biostudies-arrayexpress
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:Cancer stem cells (CSCs) comprise a small subpopulation of undifferentiated cancer cells with the ability to self-renew and give rise to the heterogeneous cancer cell lineages that form tumorous masses. Thus, tumor eradication may be greatly improved by specifically targeting CSCs, as they exhibit resistance to conventional therapy. To gain insight into the unique biology of CSCs, we developed patient-derived xenograft (PDX) tumors from ER-negative breast cancer patient tissue from which we isolated mammospheres, a method known to enrich for cells with CSC-properties. An unbiased, comparative global proteomic analysis using label-free mass spectrometry was performed on the patient tumor tissues and corresponding PDX tumors and mammospheres. Good concordance between the proteome profiles of patient tumor tissue and corresponding PDX tumors was observed. However, lower abundance of immune- and extracellular matrix-related proteins and higher abundance of proteins associated with cell-to-cell adhesion including desmosome proteins and β-catenin were observed in PDX versus patient tumors. Interestingly, analysis of proteins elevated in mammospheres vs. PDX tumors identified an enrichment of proteins associated with de novo cholesterol synthesis. The clinical relevance of increased cholesterol biosynthesis protein expression was verified in a large gene expression data set of clinical breast cancers showing correlation with shorter relapse-free survival. RNA interference and chemical inhibition of the cholesterol biosynthesis pathway reduced mammosphere formation and growth of CSCs derived from PDX tumors and cancer cell lines. Our findings identify the cholesterol biosynthesis pathway as central for CSC growth and a potential therapeutic target for CSC as well as providing an additional mechanistic explanation for the observed benefit of statins in breast cancer treatment.
2019-07-02 | PXD011222 | Pride
Project description:The origin and the contribution of breast tumor heterogeneity to its progression are not clear. We investigated the effect of a growing orthotopic tumor formed by an aggressive estrogen receptor (ER)-negative breast cancer cell line on the metastatic potential of a less aggressive ER-positive breast cancer cell line for the elucidation of how the presence of heterogeneous cancer cells might affect each other’s metastatic behavior. ER positive ZR-75-1/GFP/puro cells, resistant to puromycin and non-tumorigenic/non-metastatic without exogenous estrogen supplementation, were injected intracardiacally into mice bearing growing orthotopic tumors, formed by ER negative MDA-MB-231/GFP/Neo cells resistant to G418. A variant cell line B6, containing both estrogen-dependent and -independent cells, were isolated from GFP expressing cells in the bone marrow and re-inoculated in nude mice to generate an estrogen-independent cell line B6TC.
2011-05-25 | E-GEOD-27515 | biostudies-arrayexpress
Project description:Background: We have established a statistical approach on building a transcriptional regulatory network in silico at a global transcriptome scale. Here, we characterize clinical relevant gene activities regulated by a transcription factor-estrogen-related receptor gamma (ESRRG) via such approach. Methods: We measured gene expression relationship between ESRRG and its target gene via univariate coefficient of intrinsic dependence and Galton Pearson’s correlation coefficient. A few more bioinformatics tools were used for further investigation on ESRRG. Results: ESRRG is a negative determinant of lymphovascular invasion, lymph nodal category, stage, histological grade, nuclear pleomorphism and tubule formation in ER(+) infiltrating ductal carcinoma of breast. Interestingly, ESRRG was the only one in the final intersection of Venn Diagram analyses for determinants of those clinical indices. We established an ESRRG core network consisting of 118 probes. Both MYB and ARNT2 were up-regulated by ESRRG and in two ESRRG subnetworks (29 probes, 89 probes), respectively. We observed genes for tumor suppressive activities and responsiveness to anticancer treatments within ESRRG core network and a conserved protective role of ESRRG. Conclusions: ESRRG is a tumor suppressor typically for ER(+) breast cancer and up-regulates tumor suppressor genes mostly within ERα transcriptional regulatory network. An ESRRG core network reveals ESRRG to be a favorable marker and MYB to be the main partner for its cancer protective role during early tumor promotion. But, ARNT2 is an additional partner of ESRRG during early tumor progression. Impact: A core ESRRG transcriptional regulatory network indicates the major clinical impact of ESRRG. 181 surgical specimens of primary infiltrating ductal carcinoma (IDC) were obtained from patients who underwent surgery at National Taiwan University Hospital (NTUH) between 1998 and 2007. They include 90 ER(+) IDCs and 91 ER(-) IDCs. Tissue samples were excised, snap frozen in liquid nitrogen, and stored at -80℃. Breast cancer samples containing relatively pure cancer as defined by greater than 50% tumor cells per high-power field examined in an adjacent section of tumor sample were for this study (Lien HC, et al. Oncogene 2007; 26: 7859-71). Twenty five non-tumor samples were surgically taken from breast cancer patients in 181 IDC patients to generate 25 gene expression profiles as a control in this study. All patients had given informed consent according to the guidelines approved by the Institutional Review Board at NTUH. The matrix file linked to the bottom of this Series includes reanalyzed data from the 119 Samples of this Series and 87 Samples from Series GSE9309 and GSE17040.
2010-11-04 | E-GEOD-24124 | biostudies-arrayexpress