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In Vitro and In Vivo Analysis of B-Myb in Basal-Like Breast Cancer

ABSTRACT: The basal-like breast cancer subtype portends a poor clinical prognosis, and a defining feature of this subtype is the high expression of genes in the “proliferation signature”. B-Myb, a member of the MYB protein family of transcription factors, is highly expressed in the proliferation signature and is amplified and overexpressed in a variety of tumor types, including breast. In this report we demonstrated that B-Myb is highly expressed in basal-like breast cancer relative to the other subtypes, and B-Myb expression alone is prognostic. We also identified an association between a nonsynonymous B-Myb germline variant (S427G, rs2070235) and an increased risk of having a basal-like breast cancer among patients with breast cancer. The expression of B-Myb, or the S427G variant, was manipulated in vitro and we observed that in hTERT-immortalized normal Human Mammary Epithelial Cells, but not basal-like tumor-derived lines, cells ectopically expressing B-Myb showed increased sensitivity to DNA topoisomerase II inhibitors, but not other chemotherapeutics; in addition, microarray analyses of B-Myb overexpressing cells identified many G2/M targets as being preferentially induced. These results again suggest that B-Myb is involved in G2/M cell cycle control and that dysregulation of B-Myb may contribute to an increased sensitivity to a specific class of chemotherapeutic agents in vitro, and potentially in vivo. These data provide insight into the influence of B-Myb in human breast cancer, which is of potential clinical importance for determining disease risk and for guiding treatment. Keywords: MYB protein family of transcription factors in Breast Cancer subtype study

ORGANISM(S): Homo sapiens

PROVIDER: GSE11429 | GEO | 2009/01/07

SECONDARY ACCESSION(S): PRJNA106453

REPOSITORIES: GEO

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Transcription profiling of human basal-like breast cancer - in vitro and in vivo Analysis of B-Myb

Project description:The basal-like breast cancer subtype portends a poor clinical prognosis, and a defining feature of this subtype is the high expression of genes in the âproliferation signatureâ. B-Myb, a member of the MYB protein family of transcription factors, is highly expressed in the proliferation signature and is amplified and overexpressed in a variety of tumor types, including breast. In this report we demonstrated that B-Myb is highly expressed in basal-like breast cancer relative to the other subtypes, and B-Myb expression alone is prognostic. We also identified an association between a nonsynonymous B-Myb germline variant (S427G, rs2070235) and an increased risk of having a basal-like breast cancer among patients with breast cancer. The expression of B-Myb, or the S427G variant, was manipulated in vitro and we observed that in hTERT-immortalized normal Human Mammary Epithelial Cells, but not basal-like tumor-derived lines, cells ectopically expressing B-Myb showed increased sensitivity to DNA topoisomerase II inhibitors, but not other chemotherapeutics; in addition, microarray analyses of B-Myb overexpressing cells identified many G2/M targets as being preferentially induced. These results again suggest that B-Myb is involved in G2/M cell cycle control and that dysregulation of B-Myb may contribute to an increased sensitivity to a specific class of chemotherapeutic agents in vitro, and potentially in vivo. These data provide insight into the influence of B-Myb in human breast cancer, which is of potential clinical importance for determining disease risk and for guiding treatment. Experiment Overall Design: Reference VS. Samples

2009-01-18 | E-GEOD-11429 | biostudies-arrayexpress

MicroRNA-29c is down-regulated in basal-like breast cancers and regulates invasion and chemosensitivity

Project description:While the basal-like subtype accounts for only a small subset of all breast cancer cases, it is associated with the worst prognosis. The majority of basal-like tumors are triple-negative (ER-, PR-, and HER2-negative), and thus lack molecular targets for therapy. To identify potential molecular markers and/or pathways that are critical to the basal-like tumor phenotype, we investigated the deregulation of microRNAs in primary breast tumors from an ethnically diverse cohort of patients. Forty-four microRNAs were identified as down-regulated in basal-like tumors compared to luminal-A tumors. MicroRNA-29c (miR-29c) was the most significantly down-regulated microRNA. In breast cancer cells in vitro, miR-29c was capable of regulating phenotypes associated with basal-like tumors such as cell invasion and drug sensitivity. Exogenous expression of miR-29c sensitizes UACC 3199 to doxorubicin-induced killing, while its inhibition leads to resistance to doxorubicin-induced killing. In addition, miR-29c decreases invasiveness of UACC-3199 cells, along with down-regulation of extracellular matrix (ECM) genes (LAMC1 and COL5A2) and ECM modifying enzyme LOXL2. In addition, miR-29c directly regulates B-MYB, an oncogene over expressed in basal-like tumors and co-expression of miR-29c and B-MYB abolishes UACC 3199 sensitivity to doxorubicin. Furthermore, our work demonstrates a regulatory role for the transcription factor GATA3 in miR-29c expression in breast cancer. Our findings support a role for miR-29c in basal-like breast tumorigenesis that is linked to drug resistance.

2015-12-22 | GSE38951 | GEO

Basal-like Breast Cancer DNA copy number losses identify genes involved in genomic instability, response to therapy, and patient survival

Project description:Breast cancer is a heterogeneous disease with known tumor subtypes. In order to gain insight into the underlying etiologies of these disease subtypes, we first classified tumors according to gene expression intrinsic subtype, and second, identified subtype associated tumor genomic DNA copy number alterations (CNA) using a novel method called SWITCHdna. Most tumor subtypes showed specific CNA with Basal-like breast cancers being the most distinct and associated with loss of RB1, BRCA1, 5q11-35, and showed the greatest overall genomic instability. The common Basal-like CNA of loss of a segment of chromosome 5q11-35 contained at least three genes important for DNA repair (RAD17, RAD50, and RAP80), which were predominantly lost in pairs or all three simultaneously. Loss of two or three of these genes was associated with significantly increased genomic instability as defined by the absolute number of CNA, and poor patient survival . RNAi knockdown of RAD17, or RAD17 and RAD50, in an immortalized HMEC line caused increased sensitivity to a PARP inhibitor, or carboplatin. These data suggest mechanisms for genomic instability in Basal-like breast cancers and a biological rationale for the use of DNA repair inhibitor related therapeutics in this aggressive breast cancer subtype.

2011-11-06 | GSE10893 | GEO

The retinoblastoma gene is targeted for rearrangements in BRCA1-deficient basal-like breast cancer.

Project description:Breast tumors from BRCA1 germ line mutation carriers typically exhibit features of the basal-like molecular subtype. However, the specific genes recurrently mutated as a consequence of BRCA1 dysfunction have not been fully elucidated. In this study, we utilized gene expression profiling to molecularly subtype 577 breast tumors, including 73 breast tumors from BRCA1/2 mutation carriers. Focusing on the RB1 locus, we analyzed 33 BRCA1-mutated, 36 BRCA2-mutated and 48 non-BRCA1/2-mutated breast tumors using a custom-designed high-density oligomicroarray covering the RB1 gene. We found a strong association between the basal-like subtype and BRCA1-mutated breast tumors and the luminal B subtype and BRCA2-mutated breast tumors. RB1 was identified as a major target for genomic disruption in tumors arising in BRCA1 mutation carriers and in sporadic tumors with BRCA1 promoter-methylation, but rarely in other breast cancers. Homozygous deletions, intragenic breaks, or microdeletions were found in 33% of BRCA1-mutant tumors, 36% of BRCA1 promoter-methylated basal-like tumors, 13% of non-BRCA1 deficient basal-like tumors, and 3% of BRCA2-mutated tumors. In addition, RB1 was frequently inactivated by gross gene disruption in BRCA1-related hereditary breast cancer and BRCA1-methylated sporadic basal-like breast cancer, but rarely in BRCA2-hereditary breast cancer and non-BRCA1-deficient sporadic breast cancers. Together, our findings demonstrate the existence of genetic heterogeneity within the basal-like breast cancer subtype that is based upon BRCA1-status. Gene expression profiling of breast tumors. Dual color common reference gene expression study using 55K oligonucleotide microarrays.

2012-06-26 | E-GEOD-25307 | biostudies-arrayexpress

Indole-3-Carbinol Preferentially Target ERÎ±-Positive Breast Cancer Cells.

Project description:Indole-3-carbinol (I3C) is a natural anti-carcinogenic compound found at high concentrations in Brassica vegetables. ER-positive cell lines demonstrated the greatest sensitivity to the anti-tumor effects of I3C compared to ER-negative breast cancer cell lines. Gene expression analysis was performed to identify genes and pathways that accounted for sensitivity to I3C. Microarray analysis performed using Illumina HT-12 v4 expression arrays A total of 36 samples were analyzed with six breast cancer cell lines treated with either the vehicle control or the drug Indole-3-carbinol in triplicate. The cell lines were: MCF-7, T47D, ZR751(sensitive to the drug, apoptosis/growth arrest) and MDA-MB-231, MDA-MB-157, and MDA-MB-436 (insensitive to the drug). Sensitive cell lines are of the luminal subtype and insensitive cell lines are of the basal subtype.

2014-08-12 | E-GEOD-55897 | biostudies-arrayexpress

Identification of p63 binding regions in a p63 expressing basal-subtype breast cancer cell line, MCFDCIS.

Project description:p63 ChIP-SEQ in a p63 expressing basal-subtype breast cancer cell line, MCFDCIS and in a p63 deficient claudin-low subtype breast cancer cell line, MDA-MB-231

2016-08-11 | GSE72009 | GEO

Over-expression of miR-146a in basal-like breast cancer cells confers enhanced tumorigenic potential in association with altered p53 status

Project description:The tumor suppressor p53 is the most frequently mutated gene in human cancers, mutated in 25-30% of breast cancers. However, mutation rates differ according to breast cancer subtype, being more prevalent in aggressive estrogen receptor (ER) negative tumors, basal-like and HER2 amplified subtypes. This heterogeneity suggests that p53 may function differently across breast cancer subtypes. We used RNAi-mediated p53 knockdown (KD) and antagomir-mediated KD of microRNAs to study how gene expression and cellular response to p53 loss differ in luminal vs. basal-like breast cancer. As expected, p53 loss caused down regulation of established p53 targets (e.g. p21 and miR-34 family) and increased proliferation in both luminal and basal-like cell lines. However, some p53-dependent changes were subtype-specific, including expression of miR-134, miR-146a, and miR-181b. To study the cellular response to miR-146a upregulation in p53-impaired basal-like lines, antagomir knockdown of miR-146a was performed. KD of miR-146a caused decreased proliferation and increased apoptosis, effectively ablating the effects of p53 loss. Furthermore, we found that miR-146a upregulation decreased NF-kB expression and downregulated the NF-kB-dependent extrinsic apoptotic pathway (including TNF, FADD, and TRADD) and antagomir-mediated miR-146a KD restored expression of these components, suggesting a plausible mechanism for miR-146a-dependent cellular responses. These findings are relevant to human basal-like tumor progression in vivo, since miR-146a is highly expressed in p53-mutant basal-like breast cancers. These findings suggest that targeting miR-146a expression may have value for altering the aggressiveness of p53 mutant basal-like tumors. reference x sample

2014-06-30 | E-GEOD-52783 | biostudies-arrayexpress

Identification of p63 binding regions in a p63 expressing basal-subtype breast cancer cell line, MCFDCIS.

Project description:p63 ChIP-SEQ in a p63 expressing basal-subtype breast cancer cell line, MCFDCIS and in a p63 deficient claudin-low subtype breast cancer cell line, MDA-MB-231 p63 ChIP-SEQ on MCFDCIS and MDA-MB-231 cell lines

2016-08-11 | E-GEOD-72009 | biostudies-arrayexpress

The retinoblastoma gene is targeted for rearrangements in BRCA1-deficient basal-like breast cancer.

2012-06-27 | GSE25307 | GEO

Vimentin DNA Methylation Predicts Survival in Breast Cancer

Project description:Purpose:The Vimentin gene plays a pivotal role in epithelial-to-mesenchymal transition (EMT) and is known to be over-expressed in the prognostically poor basal-like breast cancer subtype. Recent studies have reported Vimentin DNA methylation in association with poor clinical outcomes in other solid tumors, but not in breast cancer. We therefore quantified Vimentin DNA methylation in breast tumors and matched normal pairs in association with gene expression and survival in a cohort of 83 breast cancer patients. Materials and Methods:Vimentin methylation was quantified in 14 breast cell lines, 83 breast tumors, and 57 matched normal pairs using MALDI-TOF mass spectrometry. Gene expression data via qRT-PCR in cell lines, and oligo microarray data from breast tissues was correlated with percent methylation in the Vimentin promoter. A threshold of 20 percent average methylation was set for bivariate and multivariate tests of association between methylation and tumor subtype, tumor histopathology, and survival. Results:Vimentin was differentially methylated in luminal breast cancer cell lines, and in luminal A, luminal B and HER2+ breast tumor subtypes, but was rare in basal-like cell lines and tumors. Increased methylation was strongly correlated with decreased mRNA expression in cell lines, and had a moderate inverse correlation in breast tumors. Importantly, Vimentin methylation predicted poor overall survival independent of race, subtype, stage, nodal status or estrogen receptor positivity. Conclusion:Vimentin methylation predicts overall survival in breast cancer patients and holds promise as a prognostic biomarker for guiding treatment and prophylaxis. reference x sample

2013-02-19 | E-GEOD-35629 | biostudies-arrayexpress

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