Chromatin Accessibility differentiates Invasive Lobular from Invasive Ductal Breast cancer and Dictates Response to Endocrine Treatment
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE152367 | GEO | 2022/08/31
REPOSITORIES: GEO
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Project description:Invasive lobular breast cancer (ILC) is the second most common histological sub-type of breast cancer. Although the majority of ILC are strongly hormone receptor positive and are of low-intermediate grade, they present a number of clinical challenges. These challenges include limitations in physical exam and breast imaging for early detection, decreased response to chemotherapy and prospective evidence for differences in the benefit from specific adjuvant endocrine treatment regimens when compared to invasive ductal cancer (IDC). In addition to loss of e-cadherin, ILCs possess genetic alterations that are suggestive of a unique estrogen receptor(ER) axis, including an increase in the frequency of FOXA1 mutations and decrease in GATA3 truncating mutations. We performed a randomized Phase II clinical trial, Palbociclib and Endocrine therapy for LObular breast cancer Preoperative Study (PELOP), in which patients were stratified by histological subtype and found that the magnitude of the difference between the benefit from letrozole compared tamoxifen is significantly higher in ILC versus IDC. To elucidate the mechanism underlying this divergent response we comprehensively studied the ER axis in experimental models of ILC and IDC and clinical samples and show that ILC harbors a unique ER transcriptional axis that stems from increased FOXA1 chromatin binding and an altered chromatin state. These findings provide insights to the unique pattern of response to endocrine treatment in ILC and mechanisms of resistance to endocrine treatment, and offer new treatment strategies to improve outcomes for patients with this breast cancer subtype."
2022-08-31 | GSE152360 | GEO
Project description:Invasive lobular breast cancer (ILC) is the second most common histological sub-type of breast cancer. Although the majority of ILC are strongly hormone receptor positive and are of low-intermediate grade, they present a number of clinical challenges. These challenges include limitations in physical exam and breast imaging for early detection, decreased response to chemotherapy and prospective evidence for differences in the benefit from specific adjuvant endocrine treatment regimens when compared to invasive ductal cancer (IDC). In addition to loss of e-cadherin, ILCs possess genetic alterations that are suggestive of a unique estrogen receptor(ER) axis, including an increase in the frequency of FOXA1 mutations and decrease in GATA3 truncating mutations. We performed a randomized Phase II clinical trial, Palbociclib and Endocrine therapy for LObular breast cancer Preoperative Study (PELOP), in which patients were stratified by histological subtype and found that the magnitude of the difference between the benefit from letrozole compared tamoxifen is significantly higher in ILC versus IDC. To elucidate the mechanism underlying this divergent response we comprehensively studied the ER axis in experimental models of ILC and IDC and clinical samples and show that ILC harbors a unique ER transcriptional axis that stems from increased FOXA1 chromatin binding and an altered chromatin state. These findings provide insights to the unique pattern of response to endocrine treatment in ILC and mechanisms of resistance to endocrine treatment, and offer new treatment strategies to improve outcomes for patients with this breast cancer subtype."
2022-08-31 | GSE152361 | GEO
Project description:Chromatin Accessibility differentiates Invasive Lobular from Invasive Ductal Breast cancer and Dictates Response to Endocrine Treatment
| PRJNA639109 | ENA
Project description:Chromatin Accessibility differentiates Invasive Lobular from Invasive Ductal Breast cancer and Dictates Response to Endocrine Treatment
| PRJNA639111 | ENA
Project description:Chromatin Accessibility differentiates Invasive Lobular from Invasive Ductal Breast cancer and Dictates Response to Endocrine Treatment
| PRJNA639106 | ENA
Project description:BackgroundInvasive lobular breast carcinoma (ILC), the second most prevalent histological subtype of breast cancer, exhibits unique molecular features compared with the more common invasive ductal carcinoma (IDC). While genomic and transcriptomic features of ILC and IDC have been characterized, genome-wide chromatin accessibility pattern differences between ILC and IDC remain largely unexplored.MethodsHere, we characterized tumor-intrinsic chromatin accessibility differences between ILC and IDC using primary tumors from The Cancer Genome Atlas (TCGA) breast cancer assay for transposase-accessible chromatin with sequencing (ATAC-seq) dataset.ResultsWe identified distinct patterns of genome-wide chromatin accessibility in ILC and IDC. Inferred patient-specific transcription factor (TF) motif activities revealed regulatory differences between and within ILC and IDC tumors. EGR1, RUNX3, TP63, STAT6, SOX family, and TEAD family TFs were higher in ILC, while ATF4, PBX3, SPDEF, PITX family, and FOX family TFs were higher in IDC.ConclusionsThis study reveals the distinct epigenomic features of ILC and IDC and the active TFs driving cancer progression that may provide valuable information on patient prognosis.
| S-EPMC9338552 | biostudies-literature
Project description:This set of experiments includes 38 IDCs, 21 ILCs, 2 lymphnode metastases, and 3 normal breast samples. It is designed to compare gene expression profiles of IDCs and ILCs. Total RNAs from all samples were isolated using TRIzol, amplified using optimized T7 linear amplification protocol, and labeled with Cy5. Stratagen Universal Human Reference RNA was amplified the same way and labeled with Cy3. Set of arrays organized by shared biological context, such as organism, tumors types, processes, etc. Computed
2006-01-05 | E-GEOD-3971 | biostudies-arrayexpress
Project description:This set of experiments includes 38 IDCs, 21 ILCs, 2 lymphnode metastases, and 3 normal breast samples. It is designed to compare gene expression profiles of IDCs and ILCs. Total RNAs from all samples were isolated using TRIzol, amplified using optimized T7 linear amplification protocol, and labeled with Cy5. Stratagen Universal Human Reference RNA was amplified the same way and labeled with Cy3. Set of arrays organized by shared biological context, such as organism, tumors types, processes, etc. Keywords: Logical Set
2006-01-06 | GSE3971 | GEO
Project description:Invasive lobular breast carcinoma (ILC), one of the major breast cancer histologic subtypes, exhibits unique features compared with the well-studied ductal cancer subtype (IDC). The pathognomonic feature of ILC is loss of E-cadherin, mainly caused by inactivating mutations, but the contribution of this genetic alteration to ILC-specific molecular characteristics remains largely understudied. To profile these features transcriptionally, we conducted single-cell RNA sequencing on a panel of IDC and ILC cell lines, and an IDC cell line (T47D) with CRISPR-Cas9-mediated E-cadherin knockout (KO). Inspection of intracell line heterogeneity illustrated genetically and transcriptionally distinct subpopulations in multiple cell lines and highlighted rare populations of MCF7 cells highly expressing an apoptosis-related signature, positively correlated with a preadaptation signature to estrogen deprivation. Investigation of E-cadherin KO-induced alterations showed transcriptomic membranous systems remodeling, elevated resemblance to ILCs in regulon activation, and increased sensitivity to IFNγ-mediated growth inhibition via activation of IRF1. This study reveals single-cell transcriptional heterogeneity in breast cancer cell lines and provides a resource to identify drivers of cancer progression and drug resistance. SIGNIFICANCE: This study represents a key step towards understanding heterogeneity in cancer cell lines and the role of E-cadherin depletion in contributing to the molecular features of invasive lobular breast carcinoma.
| S-EPMC7856056 | biostudies-literature
Project description:BACKGROUND:Invasive lobular breast carcinoma (ILC) is a histological subtype of breast cancer that is characterized by loss of E-cadherin and high expression of estrogen receptor alpha (ER?). In many cases, ILC is effectively treated with adjuvant aromatase inhibitors (AIs); however, acquired AI resistance remains a significant problem. METHODS:To identify underlying mechanisms of acquired anti-estrogen resistance in ILC, we recently developed six long-term estrogen-deprived (LTED) variant cell lines from the human ILC cell lines SUM44PE (SUM44; two lines) and MDA-MB-134VI (MM134; four lines). To better understand mechanisms of AI resistance in these models, we performed transcriptional profiling analysis by RNA-sequencing followed by candidate gene expression and functional studies. RESULTS:MM134 LTED cells expressed ER at a decreased level and lost growth response to estradiol, while SUM44 LTED cells retained partial ER activity. Our transcriptional profiling analysis identified shared activation of lipid metabolism across all six independent models. However, the underlying basis of this signature was distinct between models. Oxysterols were able to promote the proliferation of SUM44 LTED cells but not MM134 LTED cells. In contrast, MM134 LTED cells displayed a high expression of the sterol regulatory element-binding protein 1 (SREBP1), a regulator of fatty acid and cholesterol synthesis, and were hypersensitive to genetic or pharmacological inhibition of SREBPs. Several SREBP1 downstream targets involved in fatty acid synthesis, including FASN, were induced, and MM134 LTED cells were more sensitive to etomoxir, an inhibitor of the rate-limiting enzyme in beta-oxidation, than their respective parental control cells. Finally, in silico expression analysis in clinical specimens from a neo-adjuvant endocrine trial showed a significant association between the increase of SREBP1 expression and lack of clinical response, providing further support for a role of SREBP1 in the acquisition of endocrine resistance in breast cancer. CONCLUSIONS:Our characterization of a unique series of AI-resistant ILC models identifies the activation of key regulators of fatty acid and cholesterol metabolism, implicating lipid-metabolic processes driving estrogen-independent growth of ILC cells. Targeting these changes may prove a strategy for prevention and treatment of endocrine resistance for patients with ILC.
| S-EPMC6124012 | biostudies-literature