Chromosome 12p Amplification in Triple-Negative/<i>BRCA1-</i>Mutated Breast Cancer Associates with Emergence of Docetaxel Resistance and Carboplatin Sensitivity

Gómez-Miragaya, Jorge; Díaz-Navarro, Ander; Tonda, Raúl; Beltrán, Sergi; Palomero, Luís; Palafox, Marta; Dobrolecki, Lacey E.; Huang, Chen; Vasaikar, Suhas; Zhang, Bing; Wulf, Gerburg M.; Collado-Solé, Alejandro; Trinidad, Eva M.; Muñoz, Purificacı́on; Paré, Laia; Prat, Aleix; Bruna, Alejandra; Caldas, Carlos; Arribas, Joaquı́n; Soler-Monsó, María Teresa; Petit, Audrey; Balmañà, Judith; Cruz, Cristina; Serra, Violeta; Pujana, Miguel Ángel; Lewis, Michael T.; Puente, Xosé S.; González‐Suárez, Eva

doi:10.1158/0008-5472.can-18-3835

Cited by 19 publications

(19 citation statements)

References 50 publications

(66 reference statements)

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“…Paclitaxel is emerging as a promising drug for TNBC therapy [28,29], promoting us to explore the underlying mechanism for its therapy resistance in the current study. We selected the MDA‐MB‐231 and SUM159PT cell lines for the gain and loss of function assays, as these two cell lines had a medium level of BOP1 expression and are suitable for BOP1 overexpression or knockdown modifications (supplementary material, Figure S2A,B).…”

Section: Resultsmentioning

confidence: 99%

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BOP1 confers chemoresistance of triple‐negative breast cancer by promoting CBP‐mediated β‐catenin acetylation

Huang³

et al. 2021

The Journal of Pathology

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Chemoresistance is a major obstacle to the treatment of triple‐negative breast cancer (TNBC), which has a poor prognosis. Increasing evidence has demonstrated the essential role of cancer stem cells (CSCs) in the process of TNBC chemoresistance. However, the underlying mechanism remains unclear. In the present study, we report that block of proliferation 1 (BOP1) serves as a key regulator of chemoresistance in TNBC. BOP1 expression was significantly upregulated in chemoresistant TNBC tissues, and high expression of BOP1 correlated with shorter overall survival and relapse‐free survival in patients with TNBC. BOP1 overexpression promoted, while BOP1 downregulation inhibited the drug resistance and CSC‐like phenotype of TNBC cells in vitro and in vivo. Moreover, BOP1 activated Wnt/β‐catenin signaling by increasing the recruitment of cyclic AMP response element‐binding protein (CBP) to β‐catenin, enhancing CBP‐mediated acetylation of β‐catenin, and increasing the transcription of downstream stemness‐related genes CD133 and ALDH1A1. Notably, treating with the β‐catenin/CBP inhibitor PRI‐724 induced an enhancement of chemotherapeutic response of paclitaxel in BOP1‐overexpressing TNBC cells. These findings indicate that BOP1 is involved in chemoresistance development and might serve as a prognostic marker and therapeutic target in TNBC. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Section: Resultsmentioning

confidence: 99%

“…In the former case, an agent that can reasonably be expected to cause an anti‐tumor effect fails to do so at the very beginning of therapy. In contrast, acquired drug resistance is apparently (and implicitly) secondary to the exposure [28,30]. We further assessed whether PTX treatment regulated BOP1 expression.…”

Section: Resultsmentioning

confidence: 99%

BOP1 confers chemoresistance of triple‐negative breast cancer by promoting CBP‐mediated β‐catenin acetylation

Huang³

et al. 2021

The Journal of Pathology

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“…Treatment was interrupted once tumor size was reduced below 3 mm of diameter and reinitiated once tumors reached 6 mm of diameter. DNA methylation profiles from paired sensitive and resistant TNBC PDX and/or residual disease described previously (23,27) and human samples of origin (when available) were obtained. All resistant TNBC PDX models used in this study were maintained under in vivo selective drug pressure and they were completely resistant to docetaxel [passage 3 of resistance for all models except VHIO-98R (passage 4 of resistance)].…”

Section: Patient Characteristics and Generation Of Pdxmentioning

confidence: 99%

“…A, Unsupervised hierarchical methylation clustering using the 10,000 most variable CpGs between TNBC PDX models including sensitive (untreated), residual disease, and resistant tumors. All resistant tumors were collected at passage three of treatment, one week after last DTX treatment (23,27). Sensitive tumors were collected from a similar passage than resistant ones, to discriminate DTX-specific changes with those related with serial passages.…”

Section: Idb-02s Vs Idb-02rmentioning

confidence: 99%

The Altered Transcriptome and DNA Methylation Profiles of Docetaxel Resistance in Breast Cancer PDX Models

Gómez-Miragaya

Morán

Calleja-Cervantes

et al. 2019

Molecular Cancer Research

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Taxanes are standard therapy in clinical practice for metastatic breast cancer; however, primary or acquired chemoresistance are a common cause of mortality. Breast cancer patient-derived xenografts (PDX) are powerful tools for the study of cancer biology and drug treatment response. Specific DNA methylation patterns have been associated to different breast cancer subtypes but its association with chemoresistance remains unstudied. Aiming to elucidate docetaxel resistance mechanisms, we performed genome-wide DNA methylation in breast cancer PDX models, including luminal and triple-negative breast cancer (TNBC) models sensitive to docetaxel, their matched models after emergence of chemoresistance and residual disease after short-term docetaxel treatment. We found that DNA methylation profiles from breast cancer PDX models maintain the subtype-specific methylation patterns of clinical samples. Two main DNA methylation clusters were found in TNBC PDX and remain stable during the emergence of docetaxel resistance; however, some genes/ pathways were differentially methylated according to docetaxel response. A DNA methylation signature of resistance able to segregate TNBC based on chemotherapy response was identified. Transcriptomic profiling of selected sensitive/resistant pairs and integrative analysis with methylation data demonstrated correlation between some differentially methylated and expressed genes in docetaxel-resistant TNBC PDX models. Multiple gene expression changes were found after the emergence of docetaxel resistance in TNBC. DNA methylation and transcriptional changes identified between docetaxel-sensitive and-resistant TNBC PDX models or residual disease may have predictive value for chemotherapy response in TNBC. Implications: Subtype-specific DNA methylation patterns are maintained in breast cancer PDX models. While no global methylation changes were found, we uncovered differentially DNA methylated and expressed genes/pathways associated with the emergence of docetaxel resistance in TNBC.

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“…In humans, aneuploidy is the primary cause of spontaneous abortions and leads to severe developmental defects, such as those present in Down syndrome patients (trisomy 21) (Roper and Reeves 2006). Importantly, the aneuploid state is highly prevalent in cancer and the presence of aneuploid karyotypes correlates with poor patient prognosis (Ben-David and Amon 2019) and resistance to chemotherapy (Gómez-Miragaya et al 2019;Andor et al 2015;Birkbak et al 2011). Chemotherapy is a central therapeutic strategy for most cancer patients and resistance to therapeutic drugs leads to the failure of this treatment.…”

Section: Introductionmentioning

confidence: 99%

Aneuploidy-driven genome instability triggers resistance to chemotherapy

Ippolito

Martis

Hong

et al. 2020

Preprint

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Mitotic errors lead to aneuploidy, a condition of karyotype imbalance, frequently found in cancer cells. Alterations in chromosome copy number induce a wide variety of cellular stresses, including genome instability. Here, we show that cancer cells might exploit aneuploidy-induced genome instability to survive under conditions of selective pressure, such as chemotherapy. Resistance to chemotherapeutic drugs was dictated by the acquisition of recurrent karyotypes, indicating that gene dosage, together with mutational burden, might play a role in driving chemoresistance. Thus, our study establishes a causal link between aneuploidy-driven genome instability and chemoresistance and might explain why some chemotherapies fail to succeed.

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Chromosome 12p Amplification in Triple-Negative/BRCA1-Mutated Breast Cancer Associates with Emergence of Docetaxel Resistance and Carboplatin Sensitivity

Abstract: Non-chr12p amplified cell Chr12p amplified cell Chr12p-amplified population enrichment Patientderived xenografts Chromosome 12p-amplification is associated with docetaxel resistance and increased sensitivity to carboplatin in triple-negative breast cancer models.

Cited by 19 publications

References 50 publications

BOP1 confers chemoresistance of triple‐negative breast cancer by promoting CBP‐mediated β‐catenin acetylation

BOP1 confers chemoresistance of triple‐negative breast cancer by promoting CBP‐mediated β‐catenin acetylation

The Altered Transcriptome and DNA Methylation Profiles of Docetaxel Resistance in Breast Cancer PDX Models

Aneuploidy-driven genome instability triggers resistance to chemotherapy

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