Breast Cancer Cells Respond Differentially to Modulation of TGFβ2 Signaling after Exposure to Chemotherapy or Hypoxia

O'Brien, Siobhan; Chen, Liang; Zhong, Wenyan; Armellino, Douglas; Yu, Jiyang; Loreth, Christine; Follettie, Maximillian T.; Damelin, Marc

doi:10.1158/0008-5472.can-15-0650

Cited by 10 publications

(8 citation statements)

References 51 publications

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“…Although we did not observe signi cant changes in the expression of CD24 ( Fig. S2A), another CSC-speci c marker, previous studies have proven that CD44 expression is adequate for CSC population selection [15]. These data indicated that DOC treatment induced the enrichment of CD44 hi population which could be signi cantly inhibited by Fig.…”

Section: Decitabine Inhibits the Csc Enrichment Induced By Dab2ip Hypcontrasting

confidence: 48%

“…Several studies revealed that cells surviving after chemotherapy exhibited high CSC capacities (selfrenewal ability and CD44 expression) [9,15]. To analyze the changes of CSC population under DOC or DAC+DOC treatment, we labeled CSCs and dead cells with anti-CD44 antibodies and PI, respectively.…”

Section: Decitabine Inhibits the Csc Enrichment Induced By Dab2ip Hypmentioning

confidence: 99%

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Decitabine Reverses CSC-Induced Docetaxel Resistance via Epigenetic Regulation of DAB2IP in TNBC.

Xiong

Yang

Liu

et al. 2020

Preprint

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Background: Although docetaxel (DOC)-based chemotherapy, the standard of care for triple-negative breast cancer (TNBC), has greatly improved cancer survival, chemoresistance invariably evolves. Methods: Using TNBC and docetaxel-resistant TNBC cell lines, we established murine breast cancer xenograft models to evaluate the impact of decitabine on DOC resistance. The methylation status of DAB2IP was evaluated in 226 TNBC patients and TNBC cell lines by BSP analysis. A limiting dilution assay was performed to evaluate the tumorigenic capacity in vivo. Cellular and molecular mechanisms were demonstrated using in vivo and in vitro biochemical methods.Results: Here, we observed that a low dose of DAC significantly prevented the evolution of DOC resistance via inhibition of cancer stem cell (CSC) enrichment in TNBC. The bisulfite sequencing PCR analysis showed that DAC treatment increased DAB2IP expression via inhibition of DNA methylation in both DOC-resistant TNBC cells and tumorspheres. Loss of DAB2IP boosted the enrichment of CSCs through activation of Erk/β-catenin signaling in vitro and facilitated tumor initiation in vivo. In mouse model, TNBC tumors with inhibition of DAB2IP exhibited poor response to DOC and DOC-resistant tumors were resensitized to DOC treatment by low-dose DAC treatment in vivo. Finally, hypermethylation of DAB2IP was correlated with low expression of DAB2IP and poor outcome of TNBC patients treated with DOC-based chemotherapy. Conclusions: Collectively, we discovered that epigenetic silencing of DAB2IP is a driver of CSC enrichment, which results in the evolution of DOC resistance, and a low dose of DAC reverses DOC resistance through epigenetic re-expression of DAB2IP.

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Section: Decitabine Inhibits the Csc Enrichment Induced By Dab2ip Hypcontrasting

confidence: 48%

Section: Decitabine Inhibits the Csc Enrichment Induced By Dab2ip Hypmentioning

confidence: 99%

Decitabine Reverses CSC-Induced Docetaxel Resistance via Epigenetic Regulation of DAB2IP in TNBC.

Xiong

Yang

Liu

et al. 2020

Preprint

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“…L1CAM, ANGPTL4, CA9, VEGFA, LDHA, P4HA1, LOX, LOXL2, LOXL4) are almost all significantly upregulated in both BRC12/CD184 lo and BRC13/CD49f lo cells (S3 Table). Hypoxia is often correlated with therapeutic resistance [43,44]. In accordance with this, gene expression signatures of drug resistance can also be found in those same populations (S8 Fig).…”

Section: Discussionsupporting

confidence: 72%

High accuracy gene expression profiling of sorted cell subpopulations from breast cancer PDX model tissue

et al. 2020

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Intratumor Heterogeneity (ITH) is a functionally important property of tumor tissue and may be involved in drug resistance mechanisms. Although descriptions of ITH can be traced back to very early reports about cancer tissue, mechanistic investigations are still limited by the precision of analysis methods and access to relevant tissue sources. PDX models have provided a reproducible source of tissue with at least a partial representation of naturally occurring ITH. We investigated the properties of phenotypically distinct cell populations by Fluorescence activated cell sorting (FACS) tissue derived cells from multiple tumors from a triple negative breast cancer patient derived xenograft (PDX) model. We subsequently subjected each population to in depth gene expression analysis. Our findings suggest that process related gene expression changes (caused by tissue dissociation and FACS sorting) are restricted to Immediate Early Genes (IEGs). This allowed us to discover highly reproducible gene expression profiles of distinct cellular compartments identifiable by cell surface markers in this particular tumor model. Within the context of data from a previously published model our work suggests that gene expression profiles associated with hypoxia, stemness and drug resistance may reside in tumor subpopulations predictably growing in PDX models. This approach provides a novel opportunity for prospective mechanistic studies of ITH.

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“…Cancer initiating cells (CICs), also referred to as cancer stem cells, are recognized as a significant problem in effectively managing breast cancer. CICs are known for their resistance to chemotherapy, ability to form non-adherent mammospheres in vitro, and high tumorigenicity in vivo [ 3 , 4 , 5 , 6 , 7 ]. Standard chemotherapies (e.g., taxanes) have been shown to enrich the population of CICs in TNBC [ 7 , 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

212Pb-Labeled Antibody 225.28 Targeted to Chondroitin Sulfate Proteoglycan 4 for Triple-Negative Breast Cancer Therapy in Mouse Models

Kasten

Oliver

Kim

et al. 2018

IJMS

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Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with a poor prognosis. There is a clinical need for effective, targeted therapy strategies that destroy both differentiated TNBC cells and TNBC cancer initiating cells (CICs), as the latter are implicated in the metastasis and recurrence of TNBC. Chondroitin sulfate proteoglycan 4 (CSPG4) is overexpressed on differentiated tumor cells and CICs obtained from TNBC patient specimens, suggesting that CSPG4 may be a clinically relevant target for the imaging and therapy of TNBC. The purpose of this study was to determine whether α-particle radioimmunotherapy (RIT) targeting TNBC cells using the CSPG4-specific monoclonal antibody (mAb) 225.28 as a carrier was effective at eliminating TNBC tumors in preclinical models. To this end, mAb 225.28 labeled with 212Pb (212Pb-225.28) as a source of α-particles for RIT was used for in vitro Scatchard assays and clonogenic survival assays with human TNBC cells (SUM159 and 2LMP) grown as adherent cells or non-adherent CIC-enriched mammospheres. Immune-deficient mice bearing orthotopic SUM159 or 2LMP xenografts were injected i.v. with the targeted (225.28) or irrelevant isotype-matched control (F3-C25) mAbs, labeled with 99mTc, 125I, or 212Pb for in vivo imaging, biodistribution, or tumor growth inhibition studies. 212Pb-225.28 bound to adherent SUM159 and 2LMP cells and to CICs from SUM159 and 2LMP mammospheres with a mean affinity of 0.5 nM. Nearly ten times more binding sites per cell were present on SUM159 cells and CICs compared with 2LMP cells. 212Pb-225.28 was six to seven times more effective than 212Pb-F3-C25 at inhibiting SUM159 cell and CIC clonogenic survival (p < 0.05). Radiolabeled mAb 225.28 showed significantly higher uptake than radiolabeled mAb F3-C25 in SUM159 and 2LMP xenografts (p < 0.05), and the uptake of 212Pb-225.28 in TNBC xenografts was correlated with target epitope expression. 212Pb-225.28 caused dose-dependent growth inhibition of SUM159 xenografts; 0.30 MBq 212Pb-225.28 was significantly more effective than 0.33 MBq 212Pb-F3-C25 at inhibiting tumor growth (p < 0.01). These results suggest that CSPG4-specific 212Pb-225.28 is a useful reagent for RIT of CSPG4-expressing tumors, including metastatic TNBC.

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Breast Cancer Cells Respond Differentially to Modulation of TGFβ2 Signaling after Exposure to Chemotherapy or Hypoxia

Cited by 10 publications

References 51 publications

Decitabine Reverses CSC-Induced Docetaxel Resistance via Epigenetic Regulation of DAB2IP in TNBC.

Decitabine Reverses CSC-Induced Docetaxel Resistance via Epigenetic Regulation of DAB2IP in TNBC.

High accuracy gene expression profiling of sorted cell subpopulations from breast cancer PDX model tissue

212Pb-Labeled Antibody 225.28 Targeted to Chondroitin Sulfate Proteoglycan 4 for Triple-Negative Breast Cancer Therapy in Mouse Models

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