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Mediator of DNA damage checkpoint 1 (MDC1) is a novel estrogen receptor co-regulator in invasive lobular carcinoma of the breast

ABSTRACT: Mediator of DNA damage checkpoint 1 (MDC1) is a novel estrogen receptor co-regulator in invasive lobular carcinoma of the breast

PROVIDER: PRJNA719219 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR14132700_1.fastq.gz	Fastqsanger.gz
	SRR14132700_2.fastq.gz	Fastqsanger.gz
	SRR14132701_1.fastq.gz	Fastqsanger.gz
	SRR14132701_2.fastq.gz	Fastqsanger.gz
	SRR14132702_1.fastq.gz	Fastqsanger.gz

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Mediator of DNA damage checkpoint 1 (MDC1) is a novel estrogen receptor co-regulator in invasive lobular carcinoma of the breast

Project description:We identified MDC1 as a putative novel transcriptional co-regulator of estrogen receptor alpha (ER) in models of invasive lobular carcinoma. In this study, our goal was to define the contribution of MDC1 to regulation of the ER transcriptome in ILC cell lines versus invasive ductal carcinoma cells.

2021-05-13 | GSE171364 | GEO

Mediator of DNA Damage Checkpoint 1 (MDC1) Is a Novel Estrogen Receptor Coregulator in Invasive Lobular Carcinoma of the Breast.

Project description:Invasive lobular carcinoma (ILC) is the most common special histologic subtype of breast cancer, and nearly all ILC tumors express estrogen receptor alpha (ER). However, clinical and laboratory data suggest ILC are strongly estrogen-driven but not equally antiestrogen-sensitive. We hypothesized ILC-specific ER coregulators mediate ER functions and antiestrogen resistance in ILC, and profiled ER-associated proteins by mass spectrometry. Three ER+ ILC cell lines (MDA MB 134VI, SUM44PE, and BCK4) were compared with ER+ invasive ductal carcinoma (IDC) line data, and we examined whether siRNA of identified proteins suppressed ER-driven proliferation in ILC cells. This identified mediator of DNA damage checkpoint 1 (MDC1), a tumor suppressor in DNA damage response (DDR), as a novel ER coregulator in ILC. We confirmed ER:MDC1 interaction was specific to ILC versus IDC cells, and found MDC1 knockdown suppressed ILC cell proliferation and tamoxifen resistance. Using RNA-sequencing, we found in ILC cells MDC1 knockdown broadly dysregulates the ER transcriptome, with ER:MDC1 target genes enriched for promoter hormone response elements. Importantly, our data are inconsistent with MDC1 tumor suppressor functions in DDR, but suggest a novel oncogenic role for MDC1 as an ER coregulator. Supporting this, in breast tumor tissue microarrays, MDC1 protein was frequently low or absent in IDC, but MDC1 loss was rare in ER+ ILC. ER:MDC1 interaction and MDC1 coregulator functions may underlie ER function in ILC and serve as targets to overcome antiestrogen resistance in ILC. IMPLICATIONS: MDC1 has novel ER coregulator activity in ILC, which may underlie ILC-specific ER functions, estrogen response, and antiestrogen resistance.

| S-EPMC8349796 | biostudies-literature

Cdh1 and Pik3ca mutations cooperate to induce Immune-Related Invasive Lobular Carcinoma of the Breast

Project description:CDH1 and PIK3CA are the two most frequently mutated genes in Invasive Lobular Carcinoma (ILC) of the breast. Transcription profiling has identified molecular subtypes for ILC, one of which - Immune-Related (IR) - is associated with gene expression linked to lymphocyte and macrophage infiltration. Here we report that homozygous deletion of Cdh1 together with mutational activation of Pik3ca in mammary epithelium of genetically modified mice leads to rapid formation of IR-ILC-like tumors with immune cell infiltration, as well as gene expression signatures linked to TRegulatory (Treg) cell signaling and immune checkpoint inhibitor pathway activation. Interestingly, these tumors show enhanced Oct4-, Hif1á-, YAP-, Shh-, Rac- and Notch-dependent transcription/signaling, features in common with human IR-ILC and therefore potential targets for therapy. Gene expression profiling reveals immune infiltration and similarities to a subtype of human Invasive Lobular carcinoma.

2018-10-16 | GSE107432 | GEO

Expression data from invasive lobular carcinoma

Project description:Background: The prognostic value of histologic grade (HG) in invasive lobular carcinoma (ILC) remains uncertain, and most ILC tumors are graded as HG2. Genomic grade (GG) is a 97-gene signature that improves the prognostic value of HG. This study evaluates whether GG may overcome the limitations of HG in ILC. Methods: Gene expression data were generated from frozen tumor samples, and GG calculated according to the expression of 97 genes. The prognostic value of GG was assessed in a stratified Cox regression model for invasive disease-free survival (IDFS) and overall survival (OS).

2016-10-15 | GSE88770 | GEO

Transcription profiling of human invasive breast cancer carcinomas with different histological types and invasive lobular carcinoma

Project description:Gene expression array analysis on a series of ten different histological special types of invasive breast carcinomas (tubular, micropapillary, mucinous A, mucinous B, endocrine, apocrine, metaplastic, medullary, adenoid cystic, invasive ductal carcinoma with osteoclastic giant cells) and invasive lobular carcinoma.<br><br>Note: this experiment was reloaded into ArrayExpress in August 2010 to include mappings between raw and processed data files. It now includes additional dye-swap combined normalized data files.

2010-08-20 | E-NCMF-3 | biostudies-arrayexpress

Microarray based gene expression for invasive lobular cancer samples (RATHER)

Project description:As part of the RATHER (RAtional THERapy for breast cancer: individualized treatment for difficult-to-treat breast cancer subtypes) consortium, expression profiling of 144 untreated primary invasive lobular carcinoma (ILC) breast cancer tissues and 15 ILC cell lines was performed using microarray. Gene expression profiling of 144 ILC breast cancers and 15 ILC cell lines

2016-01-05 | E-GEOD-68057 | biostudies-arrayexpress

Microarray based gene expression for invasive lobular cancer samples (RATHER)

2016-01-05 | GSE68057 | GEO

CN profiles of invasive lobular breast cancer with variant growth pattern

Project description:CN profiles of invasive lobular breast cancer with variant growth pattern display common CN loss of chromosome 16q. Affymetrix Oncoscan arrays were performed according to the manufacturer's directions on DNA extracted from FFPE-breast cancer tissues.

2021-02-01 | GSE134844 | GEO

ERRγ mediates Tamoxifen resistance in novel models of invasive lobular breast cancer

Project description:One-third of all ER+ breast tumors treated with endocrine therapy fail to respond, and the remainder are likely to relapse in the future. Almost all data on endocrine resistance has been obtained in models of invasive ductal carcinoma (IDC). However, invasive lobular carcinomas (ILC) comprise up to 15% of newly diagnosed invasive breast cancers diagnosed each year and, while the incidence of IDC has remained relatively constant during the last 20 years, the prevalence of ILC continues to increase among postmenopausal women. We report a new model of Tamoxifen (TAM)-resistant invasive lobular breast carcinoma cells that provides novel insights into the molecular mechanisms of endocrine resistance. SUM44 cells express ER and are sensitive to the growth inhibitory effects of antiestrogens. Selection for resistance to 4-hydroxytamoxifen led to the development of the SUM44/LCCTam cell line, which exhibits decreased expression of estrogen receptor alpha (ERα) and increased expression of the estrogen-related receptor gamma (ERRγ). Knockdown of ERRγ in SUM44/LCCTam cells by siRNA restores TAM sensitivity, and overexpression of ERRγ blocks the growth-inhibitory effects of TAM in SUM44 and MDA-MB-134 VI lobular breast cancer cells. ERRγ-driven transcription is also increased in SUM44/LCCTam, and inhibition of activator protein 1 (AP1) can restore or enhance TAM sensitivity. These data support a role for ERRγ/AP1 signaling in the development of TAM resistance, and suggest that expression of ERRγ may be a marker of poor Tamoxifen response.

2008-11-01 | GSE12708 | GEO

aCGH study of lobular carcinoma in situ (LCIS) and invasive lobular carcinoma (ILC)

Project description:The identification of lobular caricnoma in situ (LCIS) in a patient's specimen confers and appreciable increased risk of development of future invasive mammary carcinoma. However the study of LCIS presents a challenge as it is usually only recognized in fixed specimens and no good in vivo or in vitro models currently exist. Recent advances in high throughput genomics have made possible comprehensive copy number analysis of lesions such as this. We have characterized LCIS on microdissected cases of archival patient samples using aCGH. We used 4 cases of LCIS with adjacent ILC. Histological sections from 4 cases of LCIS and 4 cases of ILC microdissected, DNA extracted and subjected to whole genome amplification, and aCGH.

2010-12-31 | E-GEOD-20474 | biostudies-arrayexpress

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