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BCL11A is a triple-negative breast cancer gene with critical functions in stem and progenitor cells

ABSTRACT: Triple negative breast cancer (TNBC) has poor prognostic outcome compared to other types of breast cancer1. At present the molecular and cellular mechanisms underlying TNBC pathology are not well understood1. Here we report that the transcription factor BCL11A is overexpressed in TNBC including basal-like breast cancer (BLBC) and that its genomic locus is amplified in up to 38% of BLBC tumours. BCL11A overexpression in immortalised human breast epithelial cells promotes tumour formation in xenograft models, whereas knockdown of BCL11A in TNBC cell lines suppresses their tumourigenic potential. In the DMBA-induced mouse mammary tumour model, Bcl11a is found to be essential for tumourigenesis since deletion of Bcl11a before DMBA treatment substantially decreases tumour formation, even in p53-null cells, and inactivation of Bcl11a in established tumours causes their regression. At the cellular level, BCL11A overexpression enhances clonogenicity in vitro whereas its deletion in the mouse causes a reduction in the number of mammary epithelial stem and progenitor cells. Thus, BCL11A has an important role in the genesis of TNBC and in normal mammary epithelial cells. This study highlights the importance of further investigation of BCL11A in breast cancer diagnosis and targeted therapies.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE63386 | GEO | 2014/11/18

SECONDARY ACCESSION(S): PRJNA267658

REPOSITORIES: GEO

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BCL11A: A Novel Breast Cancer Gene which Plays a Critical Role in Mammary Stem Cells and Progenitors

Project description:Triple negative breast cancer (TNBC) has poor prognostic outcome compared to other types of breast cancer1. At present the molecular and cellular mechanisms underlying TNBC pathology are not well understood1. Here we report that the transcription factor BCL11A is overexpressed in TNBC including basal-like breast cancer (BLBC) and that its genomic locus is amplified in up to 38% of BLBC tumours. BCL11A overexpression in immortalised human breast epithelial cells promotes tumour formation in xenograft models, whereas knockdown of BCL11A in TNBC cell lines suppresses their tumourigenic potential. In the DMBA-induced mouse mammary tumour model, Bcl11a is found to be essential for tumourigenesis since deletion of Bcl11a before DMBA treatment substantially decreases tumour formation, even in p53-null cells, and inactivation of Bcl11a in established tumours causes their regression. At the cellular level, BCL11A overexpression enhances clonogenicity in vitro whereas its deletion in the mouse causes a reduction in the number of mammary epithelial stem and progenitor cells. Thus, BCL11A has an important role in the genesis of TNBC and in normal mammary epithelial cells. This study highlights the importance of further investigation of BCL11A in breast cancer diagnosis and targeted therapies. [Mouse] KO is bcl11a deleted mammary stem cells. WT are mammary stem cells with intact Bcl11a. [Human] HMLE tumors overexpressing BCL11A.

2014-11-18 | E-GEOD-63386 | biostudies-arrayexpress

Identification of BCL11A targets by CHIP Seq

Project description:We have recently identified BCL11A as a key regulator of mammary stem (MaSC) and progenitor cells. Deletion of BCL11A in MaSC leads to loss of ability of those cells to engraft a cleared mammary fatpad. This biological function of BCL11A correlates with its overexpression in basal breast cancers which are thought to arise from stem and progenitor subtypes. Basal breast cancer cell lines where BCL11A is knocked down using shRNA failed to develop tumours in xenograft transplantations in mice. Therefore, BCL11A is potentially a novel target for breast cancer treatment. Microarray analysis has identified potential gene targets for BCL11A however, it is not known if these targets are directly regulated by BCL11A at the transcription level. We would like to perform CHIP-SEQ analysis on a mammary cell line using BCL11A antibody under two conditions (normal expression and overexpression of BCL11A).This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/protocol to be provided

2013-01-28 | E-ERAD-69 | biostudies-arrayexpress

Single cell RNA-Seq data for Trp53/Brca1-null premalignant mammary epithelial cells and tumor cells with a K8+ luminal origin

Project description:BRCA1 mutation-carriers are predisposed to develop Basal-like breast cancer (BLBC), and p53 mutations are present in the majority of human BLBC cases, suggesting loss of these two tumor suppressors play key roles in development of BLBC. Recent studies suggest that the majority of human breast cancers, including BLBC, may originate from mammary epithelial cells (MECs) in the luminal lineage. However, how loss of p53 and BRCA1 contributes to development of BLBC from luminal MECs remains largely elusive. We developed a novel genetic targeting and lineage tracing approach based on intraductal injection of Cre-expressing adenovirus under the control of the pan-luminal Keratin 8 (K8) promoter (Ad-K8-Cre). We performed intraductal injection of Ad-K8-Cre to female mice carrying conditional knockout alleles of Brca1 (Brca1L) and Trp53 (Trp53L). The injected females developed mammary tumors similar to human BLBC within 12 months after injection. Here we characterized MECs targeted by Ad-K8-Cre at different time points after the intraductal injection, as well as mammary tumors developed in this model, by single cell expression analysis.

2019-06-27 | GSE130453 | GEO

Microarray expression profiling data for Trp53/Brca1-null mammary tumors derived from K8+ luminal cells

Project description:BRCA1 mutation-carriers are predisposed to develop Basal-like breast cancer (BLBC), and p53 mutations are present in the majority of human BLBC cases, suggesting loss of these two tumor suppressors play key roles in development of BLBC. Recent studies suggest that the majority of human breast cancers, including BLBC, may originate from mammary epithelial cells (MECs) in the luminal lineage. However, how loss of p53 and BRCA1 contributes to development of BLBC from luminal MECs remains largely elusive. We developed a novel genetic targeting and lineage tracing approach based on intraductal injection of Cre-expressing adenovirus under the control of the pan-luminal Keratin 8 (K8) promoter (Ad-K8-Cre). We performed intraductal injection of Ad-K8-Cre to female mice carrying conditional knockout alleles of Brca1 and Trp53. The injected females developed mammary tumors within 12 months after injection. Microarray expression profiling of these tumors showed that they most closely resembled human BLBC.

2019-06-27 | GSE114787 | GEO

RNA-Seq data for Trp53/Brca1-null premalignant mammary epithelial cells with a K8+ luminal origin

2019-06-27 | GSE126761 | GEO

MicroRNA profiling of the developing mammary gland identifies miR-184 as a candidate breast tumour suppressor gene (Affymetrix)

Project description:The study of mammalian development has offered many insights into the molecular aetiology of cancer. We previously used analysis of mammary morphogenesis to discover a critical role for GATA-3 in mammary developmental and carcinogenesis. In recent years an important role for MicroRNAs (miRNAs) in a myriad of cellular processes in development and in oncogenesis has emerged. In this study, microRNA profiling of stromal and epithelial cellular subsets microdissected from the developing mouse mammary gland revealed many microRNAs with expression restricted to various cellular subsets. MicroRNA-184 (miR-184) was exclusively expressed in epithelial cells and markedly upregulated during differentiation of the proliferative, invasive cells of the pubertal terminal end bud (TEB) into ductal epithelial cells in vivo and in FACS-sorted mammary stem cells (MaSCs) versus luminal epithelial cells. miR-184 expression was silenced in mouse tumour models compared to non-transformed epithelium and in a majority of breast cancer cell line models. Ectopic reactivation of miR-184 inhibited the proliferation and self-renewal of metastatic triple negative breast cancer (TNBC) cell lines in vitro and delayed tumour formation and reduced metastasis in vivo. Gene expression studies uncovered multi-factorial direct regulation of genes in the AKT/mTORC1 pathway by miR-184. In clinical breast cancer tissues, expression of miR-184 is lost in primary TNBCs while the miR-184 promoter is methylated in a subset of lymph node metastases from TNBC patients. These studies elucidated a new layer of regulation in the PI3K/AKT/mTOR pathway with relevance to mammary development and tumour proliferation and metastasis.

2015-10-01 | GSE62259 | GEO

MicroRNA profiling of the developing mammary gland identifies miR-184 as a candidate breast tumour suppressor gene (miRNA)

2015-10-01 | GSE62260 | GEO

Autophagy Deficiency Promotes Triple-Negative Breast Cancer Resistance to T Cell-Mediated Cytotoxicity by Blocking Tenascin-C Degradation

Project description:Most triple-negative breast cancer (TNBC) patients fail to respond to T cell-mediated immunotherapies. Unfortunately, the molecular determinants are still poorly understood. Breast cancer is the disease genetically linked to a deficiency in autophagy. Here, we show that autophagy promotes tumour immune response, and autophagy defects inhibit T cell-mediated killing in TNBC tumours. Mechanistically, we identify Tenascin-C as a strong candidate for autophagy deficiency-mediated immunosuppression, in which Tenascin-C is Lys63-ubiquitinated by Skp2, particularly at Lys924 and Lys1882, thus promoting its recognition by p62 and leading to its selective autophagic degradation. High Tenascin-C expression is associated with poor prognosis and inversely correlated with LC3B expression and CD8+ T cells in TNBC patients. More importantly, inhibition of Tenascin-C in autophagy-impaired TNBC cells sensitizes T cell-mediated tumour killing and improves antitumour effects of single anti-PD1/PD-L1 therapy. Our results provide a potential strategy against TNBC with the combination of Tenascin-C blockade and immune checkpoint inhibitors.

2020-08-05 | PXD019947 | Pride

Autophagy Deficiency Promotes Triple-Negative Breast Cancer Resistance to T Cell-Mediated Cytotoxicity by Blocking Tenascin-C Degradation

2020-08-05 | PXD019946 | Pride

Somatic loss of WWOX is associated with TP53 perturbation in basal-like breast cancer

Project description:Inactivation of WW domain-containing oxidoreductase (WWOX), the gene product of the common fragile site FRA16D, is a common event in breast cancer and is associated with worse prognosis of triple-negative breast cancer (TNBC) and basal-like breast cancer (BLBC). Despite recent progress, the role of WWOX in driving breast carcinogenesis remains unknown. Here we report that ablation of Wwox in mammary tumor-susceptible mice results in increased tumorigenesis, and that the resultant tumors resemble human BLBC. Interestingly, copy number loss of Trp53 and downregulation of its transcript levels were observed in the Wwox knockout tumors. Moreover, tumors isolated from Wwox and Trp53 mutant mice were indistinguishable histologically and transcriptionally. Finally, we find that deletion of TP53 and WWOX co-occurred and is associated with poor survival of breast cancer patients. Altogether, our data uncover an essential role for WWOX as a bona fide breast cancer tumor suppressor through the maintenance of p53 stability.

2019-05-17 | GSE117387 | GEO

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