Interaction of Developmental Transcription Factor HOXC11 with Steroid Receptor Coactivator SRC-1 Mediates Resistance to Endocrine Therapy in Breast Cancer

McIlroy, Marie; McCartan, Damian; Early, Sarah A.; Gaora, Peadar Ó; Hill, A. D. K.; Young, Leonie S.

doi:10.1158/0008-5472.can-09-3713

Cited by 67 publications

(84 citation statements)

References 24 publications

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“…Among these we should mention NCOA1 (nuclear receptor coactivator (1), a transcriptional coactivator belonging to the SRC family which is deregulated in breast and prostatic cancer and may potentiate gene expression by acting as a coactivator for nuclear hormone receptors and other transcription factors (TF) [44][45][46][47][48][49][50][51][52][53][54][55]; and ROCK2, a serine/threonine kinase member of the Rho pathway, involved in cell adhesion, migration, invasion, and mitosis [56][57][58][59], which may be a potential therapeutic target in human cancer cells and animal models [60][61][62][63][64][65][66][67][68].…”

Section: Discussionmentioning

confidence: 99%

Chromosome 2p gain in monoclonal B‐cell lymphocytosis and in early stage chronic lymphocytic leukemia

et al. 2012

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Recent studies have described chromosome 2p gain as a recurrent lesion in chronic lymphocytic leukemia (CLL). We investigated the 2p gain and its relationship with common prognostic biomarkers in a prospective series of 69 clinical monoclonal B-cell lymphocytosis (cMBL) and 218 early stage (Binet A) CLL patients. The 2p gain was detected by FISH in 17 patients (6%, 16 CLL, and 1 cMBL) and further characterized by single nucleotide polymorphism-array. Overall, unfavorable cytogenetic deletions, i.e., del(11)(q23) and del(17)(p13) (P 5 0.002), were significantly more frequent in 2p gain cases, as well as unmutated status of IGHV (P < 1 3 10 24 ) and CD38 (P < 1 3 10 24 ) and ZAP-70 positive expression (P 5 0.003). Furthermore, 2p gain patients had significantly higher utilization of stereotyped B-cell receptors compared with 2p negative patients (P 5 0.009), and the incidence of stereotyped subset #1 in 2p gain patients was significantly higher than that found in the remaining CLLs (P 5 0.031). Transcriptional profiling analysis identified several genes significantly upregulated in 2p gain CLLs, most of which mapped to 2p. Among these, NCOA1 and ROCK2 are known for their involvement in tumor progression in several human cancers, whereas among those located in different chromosomes, CAV1 at 7q31.1 has been recently identified to play a critical role in CLL progression. Thus, 2p gain can be present since the early stages of the disease, particularly in those cases characterized by other poor prognosis markers. The finding of genes upregulated in the cells with 2p gain provides new insights to define the pathogenic role of this lesion. Am. J. Hematol. 88:24-31, 2013. V

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Section: Discussionmentioning

confidence: 99%

Chromosome 2p gain in monoclonal B‐cell lymphocytosis and in early stage chronic lymphocytic leukemia

et al. 2012

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“…LY2 cells were steroid depleted for 72 hours, then treated with vehicle or 4OHT for 45 minutes, and ChIP analysis was carried out as previously described (4). Cell lysates were quantified after shearing using a Nanodrop (Thermo Scientific) to ensure equal starting material in each sample.…”

Section: Chip Assay and Pcrmentioning

confidence: 99%

“…More recently, a steroid-independent role for SRC-1 has been recognized and the coactivator has been shown to interact with other transcription factors including members of the Ets family, Ets2 and PEA3 (2,3) and the developmental protein HOXC11 (4). SRC-1, a member of the p160 family of steroid coactivator proteins, is a master transcriptional regulator.…”

Section: Introductionmentioning

confidence: 99%

“…There is now substantial evidence that SRC-1 is central to the ability of endocrine tumors to adapt and overcome targeted therapy (4,6,7). Though other members of the p160 family, including SRC-2 (GRIP1/TIF2/NCoA2) and SRC-3 (AIB1/ACTR/RAC-3/pCIP/TRAM-1/NCoA3), have been investigated in endocrine-related cancer (8), a specific role for SRC-1 in the development of metastatic disease has been described (9,10).…”

Section: Introductionmentioning

confidence: 99%

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Global Gene Repression by the Steroid Receptor Coactivator SRC-1 Promotes Oncogenesis

et al. 2014

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Transcriptional control is the major determinant of cell fate. The steroid receptor coactivator (SRC)-1 enhances the activity of the estrogen receptor in breast cancer cells, where it confers cell survival benefits. Here, we report that a global analysis of SRC-1 target genes suggested that SRC-1 also mediates transcriptional repression in breast cancer cells. Combined SRC-1 and HOXC11 ChIPseq analysis identified the differentiation marker, CD24, and the apoptotic protein, PAWR, as direct SRC-1/HOXC11 suppression targets. Reduced expression of both CD24 and PAWR was associated with disease progression in patients with breast cancer, and their expression was suppressed in metastatic tissues. Investigations in endocrine-resistant breast cancer cell lines and SRC-1 À/À /PyMT mice confirmed a role for SRC-1 and HOXC11 in downregulation of CD24 and PAWR. Through bioinformatic analysis and liquid chromatography/mass spectrometry, we identified AP1 proteins and Jumonji domain containing 2C (JMD2C/KDM4C), respectively, as members of the SRC-1 interactome responsible for transcriptional repression. Our findings deepen the understanding of how SRC-1 controls transcription in breast cancers. Cancer Res; 74(9); 2533-44. Ó2014 AACR.

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“…This overlapping implies in sis action of HOTAIR in breast cancer besides its established in trans action via binding to PRC2 (Gupta et al ., 2010; Zhuang et al ., 2015). This notion is appealing because HOXC11 promotes breast cancer and the importance of PRC2 to HOTAIR functions has been challenged recently (McIlroy et al ., 2010; Portoso et al ., 2017). Secondly, the HOTAIR‐N‐HOXC11 region contains a CpG island with a CpG count of 160 assigned by the UCSC Genome Browser (Kent et al ., 2002).…”

Section: Discussionmentioning

confidence: 99%

Induction of a novel isoform of the lncRNA HOTAIR in Claudin‐low breast cancer cells attached to extracellular matrix

Zhuang

et al. 2017

Molecular Oncology

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Elevated overexpression of the lncRNA HOTAIR mediates invasion and metastasis in breast cancer. In an apparent paradox, we observed low expression of HOTAIR in the invasive Claudin‐low MDA‐MB‐231 and Hs578T cells in two‐dimensional culture (2D). However, HOTAIR expression exhibited robust induction in laminin‐rich extracellular matrix‐based three‐dimensional organotypic culture (lrECM 3D) over that in 2D culture. Induction of HOTAIR required intact ECM signaling, namely integrin α2 and SRC kinase activity. Moreover, invasive growth was suppressed by HOTAIR‐specific siRNA. Induction of HOTAIR in lrECM 3D culture resulted from the activation of a novel isoform of HOTAIR (HOTAIR‐N) whose transcription is started from the first intron of the HOXC11 gene. The HOTAIR‐N promoter exhibited increased trimethylation of histone H3 lysine 4, a histone marker of active transcription, and binding of BRD4, a reader of transcriptionally active histone markers. Inhibition of BRD4 substantially reduced the expression of HOTAIR in lrECM 3D culture. In summary, our results indicate that HOTAIR expression is activated by BRD4 binding to a novel HOTAIR‐N promoter in Claudin‐low breast cancer cells that are attached to ECM. Induction of HOTAIR is required for invasive growth of Claudin‐low breast cancer cells in lrECM 3D culture.

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Interaction of Developmental Transcription Factor HOXC11 with Steroid Receptor Coactivator SRC-1 Mediates Resistance to Endocrine Therapy in Breast Cancer

Cited by 67 publications

References 24 publications

Chromosome 2p gain in monoclonal B‐cell lymphocytosis and in early stage chronic lymphocytic leukemia

Chromosome 2p gain in monoclonal B‐cell lymphocytosis and in early stage chronic lymphocytic leukemia

Global Gene Repression by the Steroid Receptor Coactivator SRC-1 Promotes Oncogenesis

Induction of a novel isoform of the lncRNA HOTAIR in Claudin‐low breast cancer cells attached to extracellular matrix

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