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1.
PLoS Genet ; 17(11): e1009876, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34762647

RESUMO

A PI3Kα-selective inhibitor has recently been approved for use in breast tumors harboring mutations in PIK3CA, the gene encoding p110α. Preclinical studies have suggested that the PI3K/AKT/mTOR signaling pathway influences stemness, a dedifferentiation-related cellular phenotype associated with aggressive cancer. However, to date, no direct evidence for such a correlation has been demonstrated in human tumors. In two independent human breast cancer cohorts, encompassing nearly 3,000 tumor samples, transcriptional footprint-based analysis uncovered a positive linear association between transcriptionally-inferred PI3K/AKT/mTOR signaling scores and stemness scores. Unexpectedly, stratification of tumors according to PIK3CA genotype revealed a "biphasic" relationship of mutant PIK3CA allele dosage with these scores. Relative to tumor samples without PIK3CA mutations, the presence of a single copy of a hotspot PIK3CA variant was associated with lower PI3K/AKT/mTOR signaling and stemness scores, whereas the presence of multiple copies of PIK3CA hotspot mutations correlated with higher PI3K/AKT/mTOR signaling and stemness scores. This observation was recapitulated in a human cell model of heterozygous and homozygous PIK3CAH1047R expression. Collectively, our analysis (1) provides evidence for a signaling strength-dependent PI3K-stemness relationship in human breast cancer; (2) supports evaluation of the potential benefit of patient stratification based on a combination of conventional PI3K pathway genetic information with transcriptomic indices of PI3K signaling activation.

2.
Cancer Res ; 2021 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-34625424

RESUMO

Hyperpolarized 13C-magnetic resonance imaging (MRI) is an emerging tool for probing tissue metabolism by measuring 13C-label exchange between intravenously injected hyperpolarized [1-13C]pyruvate and endogenous tissue lactate. Here we demonstrate that hyperpolarized 13C-MRI can be used to detect early response to neoadjuvant therapy in breast cancer. Seven patients underwent multiparametric 1H-MRI and hyperpolarized 13C-MRI before and 7-11 days after commencing treatment. An increase in the lactate-to-pyruvate ratio of ~20% identified three patients who, following 5-6 cycles of treatment, showed pathological complete response. This ratio correlated with gene expression of the pyruvate transporter MCT1, and lactate dehydrogenase A (LDHA), the enzyme catalyzing label exchange between pyruvate and lactate. Analysis of ~2000 breast tumors showed that overexpression of LDHA and the hypoxia marker CAIX were associated with reduced relapse-free and overall survival. Hyperpolarized 13C-MRI represents a promising method for monitoring very early treatment response in breast cancer and has demonstrated prognostic potential.

3.
Oncogene ; 2021 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-34703030

RESUMO

Intratumoral heterogeneity has been described for various tumor types and models of human cancer, and can have profound effects on tumor progression and drug resistance. This study describes an in-depth analysis of molecular and functional heterogeneity among subclonal populations (SCPs) derived from a single triple-negative breast cancer cell line, including copy number analysis, whole-exome and RNA sequencing, proteome analysis, and barcode analysis of clonal dynamics, as well as functional assays. The SCPs were found to have multiple unique genetic alterations and displayed significant variation in anchorage independent growth and tumor forming ability. Analyses of clonal dynamics in SCP mixtures using DNA barcode technology revealed selection for distinct clonal populations in different in vitro and in vivo environmental contexts, demonstrating that in vitro propagation of cancer cell lines using different culture conditions can contribute to the establishment of unique strains. These analyses also revealed strong enrichment of a single SCP during the development of xenograft tumors in immune-compromised mice. This SCP displayed attenuated interferon signaling in vivo and reduced sensitivity to the antiproliferative effects of type I interferons. Reduction in interferon signaling was found to provide a selective advantage within the xenograft microenvironment specifically. In concordance with the previously described role of interferon signaling as tumor suppressor, these findings suggest that similar selective pressures may be operative in human cancer and patient-derived xenograft models.

4.
NPJ Precis Oncol ; 5(1): 83, 2021 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-34535742

RESUMO

Circulating tumor DNA (ctDNA) sequencing studies could provide novel insights into the molecular pathology of cancer in sub-Saharan Africa. In 15 patient plasma samples collected at the time of diagnosis as part of the Ghana Breast Health Study and unselected for tumor grade and subtype, ctDNA was detected in a majority of patients based on whole- genome sequencing at high (30×) and low (0.1×) depths. Breast cancer driver copy number alterations were observed in the majority of patients.

5.
Nat Commun ; 12(1): 5406, 2021 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-34518533

RESUMO

DNA methylation is aberrant in cancer, but the dynamics, regulatory role and clinical implications of such epigenetic changes are still poorly understood. Here, reduced representation bisulfite sequencing (RRBS) profiles of 1538 breast tumors and 244 normal breast tissues from the METABRIC cohort are reported, facilitating detailed analysis of DNA methylation within a rich context of genomic, transcriptional, and clinical data. Tumor methylation from immune and stromal signatures are deconvoluted leading to the discovery of a tumor replication-linked clock with genome-wide methylation loss in non-CpG island sites. Unexpectedly, methylation in most tumor CpG islands follows two replication-independent processes of gain (MG) or loss (ML) that we term epigenomic instability. Epigenomic instability is correlated with tumor grade and stage, TP53 mutations and poorer prognosis. After controlling for these global trans-acting trends, as well as for X-linked dosage compensation effects, cis-specific methylation and expression correlations are uncovered at hundreds of promoters and over a thousand distal elements. Some of these targeted known tumor suppressors and oncogenes. In conclusion, this study demonstrates that global epigenetic instability can erode cancer methylomes and expose them to localized methylation aberrations in-cis resulting in transcriptional changes seen in tumors.


Assuntos
Neoplasias da Mama/genética , Metilação de DNA , Epigênese Genética , Epigenômica/métodos , Regulação Neoplásica da Expressão Gênica , Estudos de Coortes , Ilhas de CpG/genética , Replicação do DNA/genética , Feminino , Genoma Humano/genética , Instabilidade Genômica/genética , Genômica/métodos , Humanos , Células MCF-7 , Mutação , Regiões Promotoras Genéticas/genética , Análise de Sobrevida
6.
Comput Methods Programs Biomed ; 208: 106261, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34289437

RESUMO

BACKGROUND AND OBJECTIVES: Deep learning is being increasingly used for deformable image registration and unsupervised approaches, in particular, have shown great potential. However, the registration of abdominopelvic Computed Tomography (CT) images remains challenging due to the larger displacements compared to those in brain or prostate Magnetic Resonance Imaging datasets that are typically considered as benchmarks. In this study, we investigate the use of the commonly used unsupervised deep learning framework VoxelMorph for the registration of a longitudinal abdominopelvic CT dataset acquired in patients with bone metastases from breast cancer. METHODS: As a pre-processing step, the abdominopelvic CT images were refined by automatically removing the CT table and all other extra-corporeal components. To improve the learning capabilities of the VoxelMorph framework when only a limited amount of training data is available, a novel incremental training strategy is proposed based on simulated deformations of consecutive CT images in the longitudinal dataset. This devised training strategy was compared against training on simulated deformations of a single CT volume. A widely used software toolbox for deformable image registration called NiftyReg was used as a benchmark. The evaluations were performed by calculating the Dice Similarity Coefficient (DSC) between manual vertebrae segmentations and the Structural Similarity Index (SSIM). RESULTS: The CT table removal procedure allowed both VoxelMorph and NiftyReg to achieve significantly better registration performance. In a 4-fold cross-validation scheme, the incremental training strategy resulted in better registration performance compared to training on a single volume, with a mean DSC of 0.929±0.037 and 0.883±0.033, and a mean SSIM of 0.984±0.009 and 0.969±0.007, respectively. Although our deformable image registration method did not outperform NiftyReg in terms of DSC (0.988±0.003) or SSIM (0.995±0.002), the registrations were approximately 300 times faster. CONCLUSIONS: This study showed the feasibility of deep learning based deformable registration of longitudinal abdominopelvic CT images via a novel incremental training strategy based on simulated deformations.


Assuntos
Aprendizado Profundo , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Software , Tomografia Computadorizada por Raios X
7.
EMBO Mol Med ; 13(9): e13189, 2021 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-34254730

RESUMO

Advances in sequencing technology have enabled the genomic and transcriptomic characterization of human malignancies with unprecedented detail. However, this wealth of information has been slow to translate into clinically meaningful outcomes. Different models to study human cancers have been established and extensively characterized. Using these models, functional genomic screens and pre-clinical drug screening platforms have identified genetic dependencies that can be exploited with drug therapy. These genetic dependencies can also be used as biomarkers to predict response to treatment. For many cancers, the identification of such biomarkers remains elusive. In this review, we discuss the development and characterization of models used to study human cancers, RNA interference and CRISPR screens to identify genetic dependencies, large-scale pharmacogenomics studies and drug screening approaches to improve pre-clinical drug screening and biomarker discovery.


Assuntos
Genômica , Neoplasias , Biomarcadores , Avaliação Pré-Clínica de Medicamentos , Genoma , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética
8.
Semin Cancer Biol ; 2021 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-34256129

RESUMO

Whole-genome sequencing either alone or in combination with whole-transcriptome sequencing has started to be used to analyze clinical tumor samples to improve diagnosis, provide risk stratification, and select patient-specific therapies. Compared with current genomic testing strategies, largely focused on small number of genes tested individually or targeted panels, whole-genome and transcriptome sequencing (WGTS) provides novel opportunities to identify and report a potentially much larger number of actionable alterations with diagnostic, prognostic, and/or predictive impact. Such alterations include point mutations, indels, copy- number aberrations and structural variants, but also germline variants, fusion genes, noncoding alterations and mutational signatures. Nevertheless, these comprehensive tests are accompanied by many challenges ranging from the extent and diversity of sequence alterations detected by these methods to the complexity and limited existing standardization in interpreting them. We describe the challenges of WGTS interpretation and the opportunities with comprehensive genomic testing.

9.
Breast Cancer Res ; 23(1): 66, 2021 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-34120626

RESUMO

BACKGROUND: Normal human breast tissues are a heterogeneous mix of epithelial and stromal subtypes in different cell states. Delineating the spectrum of cellular heterogeneity will provide new insights into normal cellular properties within the breast tissue that might become dysregulated in the initial stages of cancer. Investigation of surface marker expression provides a valuable approach to resolve complex cell populations. However, the majority of cell surface maker expression of primary breast cells have not been investigated. METHODS: To determine the differences in expression of a range of uninvestigated cell surface markers between the normal breast cell subpopulations, primary human breast cells were analysed using high-throughput flow cytometry for the expression of 242 cell surface proteins in conjunction with EpCAM/CD49f staining. RESULTS: We identified 35 surface marker proteins expressed on normal breast epithelial and/or stromal subpopulations that were previously unreported. We also show multiple markers were equally expressed in all cell populations (e.g. CD9, CD59, CD164) while other surface markers were confirmed to be enriched in different cell lineages: CD24, CD227 and CD340 in the luminal compartment, CD10 and CD90 in the basal population, and CD34 and CD140b on stromal cells. CONCLUSIONS: Our dataset of CD marker expression in the normal breast provides better definition for breast cellular heterogeneity.

10.
NPJ Breast Cancer ; 7(1): 73, 2021 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099718

RESUMO

The biology of breast cancer response to neoadjuvant therapy is underrepresented in the literature and provides a window-of-opportunity to explore the genomic and microenvironment modulation of tumours exposed to therapy. Here, we characterised the mutational, gene expression, pathway enrichment and tumour-infiltrating lymphocytes (TILs) dynamics across different timepoints of 35 HER2-negative primary breast cancer patients receiving neoadjuvant eribulin therapy (SOLTI-1007 NEOERIBULIN-NCT01669252). Whole-exome data (N = 88 samples) generated mutational profiles and candidate neoantigens and were analysed along with RNA-Nanostring 545-gene expression (N = 96 samples) and stromal TILs (N = 105 samples). Tumour mutation burden varied across patients at baseline but not across the sampling timepoints for each patient. Mutational signatures were not always conserved across tumours. There was a trend towards higher odds of response and less hazard to relapse when the percentage of subclonal mutations was low, suggesting that more homogenous tumours might have better responses to neoadjuvant therapy. Few driver mutations (5.1%) generated putative neoantigens. Mutation and neoantigen load were positively correlated (R2 = 0.94, p = <0.001); neoantigen load was weakly correlated with stromal TILs (R2 = 0.16, p = 0.02). An enrichment in pathways linked to immune infiltration and reduced programmed cell death expression were seen after 12 weeks of eribulin in good responders. VEGF was downregulated over time in the good responder group and FABP5, an inductor of epithelial mesenchymal transition (EMT), was upregulated in cases that recurred (p < 0.05). Mutational heterogeneity, subclonal architecture and the improvement of immune microenvironment along with remodelling of hypoxia and EMT may influence the response to neoadjuvant treatment.

11.
Semin Cancer Biol ; 2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34119643

RESUMO

Interrogating the tumor genome in its entirety by whole-genome sequencing (WGS) offers an unprecedented insight into the biology and pathogenesis of cancer, with potential impact on diagnostics, prognostication and therapy selection. WGS is able to detect sequence as well as structural variants and thereby combines central domains of cytogenetics and molecular genetics. Given the potential of WGS in directing targeted therapeutics and clinical decision-making, we envision a gradual transition of the method from research to clinical routine. This review is one out of three within this issue aimed at facilitating this effort, by discussing in-depth analytical validation, clinical interpretation and clinical utility of WGS. The review highlights the requirements for implementing, validating and maintaining a clinical WGS pipeline to obtain high-quality patient-specific data in accordance with the local regulatory landscape. Every step of the WGS pipeline, which includes DNA extraction, library preparation, sequencing, bioinformatics analysis, and data storage, is considered with respect to its logistics, necessities, potential pitfalls, and the required quality management. WGS is likely to drive clinical diagnostics and patient care forward, if requirements and challenges of the technique are recognized and met.

12.
Sci Signal ; 14(688)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34158398

RESUMO

Unlike early transcriptional responses to mitogens, later events are less well-characterized. Here, we identified delayed down-regulated genes (DDGs) in mammary cells after prolonged treatment with epidermal growth factor (EGF). The expression of these DDGs was low in mammary tumors and correlated with prognosis. The proteins encoded by several DDGs directly bind to and inactivate oncoproteins and might therefore act as tumor suppressors. The transcription factor teashirt zinc finger homeobox 2 (TSHZ2) is encoded by a DDG, and we found that overexpression of TSHZ2 inhibited tumor growth and metastasis and accelerated mammary gland development in mice. Although the gene TSHZ2 localizes to a locus (20q13.2) that is frequently amplified in breast cancer, we found that hypermethylation of its promoter correlated with down-regulation of TSHZ2 expression in patients. Yeast two-hybrid screens and protein-fragment complementation assays in mammalian cells indicated that TSHZ2 nucleated a multiprotein complex containing PRC1/Ase1, cyclin B1, and additional proteins that regulate cytokinesis. TSHZ2 increased the inhibitory phosphorylation of PRC1, a key driver of mitosis, mediated by cyclin-dependent kinases. Furthermore, similar to the tumor suppressive transcription factor p53, TSHZ2 inhibited transcription from the PRC1 promoter. By recognizing DDGs as a distinct group in the transcriptional response to EGF, our findings uncover a group of tumor suppressors and reveal a role for TSHZ2 in cell cycle regulation.

13.
STAR Protoc ; 2(3): 100608, 2021 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-34189473

RESUMO

13C nuclear spin hyperpolarization can increase the sensitivity of detection in an MRI experiment by more than 10,000-fold. 13C magnetic resonance spectroscopic imaging (MRSI) of hyperpolarized 13C label exchange between injected [1-13C]pyruvate and the endogenous tumor lactate pool can be used clinically to assess tumor grade and response to treatment. We describe here an experimental protocol for using this technique in patient-derived and established cell line xenograft models of breast cancer in the mouse. For complete details on the use and execution of this protocol, please refer to Ros et al. (2020).

14.
Semin Cancer Biol ; 2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34175442

RESUMO

Precision diagnostics is one of the two pillars of precision medicine. Sequencing efforts in the past decade have firmly established cancer as a primarily genetically driven disease. This concept is supported by therapeutic successes aimed at particular pathways that are perturbed by specific driver mutations in protein-coding domains and reflected in three recent FDA tissue agnostic cancer drug approvals. In addition, there is increasing evidence from studies that interrogate the entire genome by whole-genome sequencing that acquired global and complex genomic aberrations including those in non-coding regions of the genome might also reflect clinical outcome. After addressing technical, logistical, financial and ethical challenges, national initiatives now aim to introduce clinical whole-genome sequencing into real-world diagnostics as a rational and potentially cost-effective tool for response prediction in cancer and to identify patients who would benefit most from 'expensive' targeted therapies and recruitment into clinical trials. However, so far, this has not been accompanied by a systematic and prospective evaluation of the clinical utility of whole-genome sequencing within clinical trials of uniformly treated patients of defined clinical outcome. This approach would also greatly facilitate novel predictive biomarker discovery and validation, ultimately reducing size and duration of clinical trials and cost of drug development. This manuscript is the third in a series of three to review and critically appraise the potential and challenges of clinical whole-genome sequencing in solid tumors and hematological malignancies.

15.
Cell Syst ; 12(5): 401-418.e12, 2021 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-33932331

RESUMO

One goal of precision medicine is to tailor effective treatments to patients' specific molecular markers of disease. Here, we used mass cytometry to characterize the single-cell signaling landscapes of 62 breast cancer cell lines and five lines from healthy tissue. We quantified 34 markers in each cell line upon stimulation by the growth factor EGF in the presence or absence of five kinase inhibitors. These data-on more than 80 million single cells from 4,000 conditions-were used to fit mechanistic signaling network models that provide insight into how cancer cells process information. Our dynamic single-cell-based models accurately predicted drug sensitivity and identified genomic features associated with drug sensitivity, including a missense mutation in DDIT3 predictive of PI3K-inhibition sensitivity. We observed similar trends in genotype-drug sensitivity associations in patient-derived xenograft mouse models. This work provides proof of principle that patient-specific single-cell measurements and modeling could inform effective precision medicine strategies.

16.
Cell Death Differ ; 28(9): 2778-2796, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33963313

RESUMO

The prognosis of early breast cancer (BC) relies on cell autonomous and immune parameters. The impact of the intestinal microbiome on clinical outcome has not yet been evaluated. Shotgun metagenomics was used to determine the composition of the fecal microbiota in 121 specimens from 76 early BC patients, 45 of whom were paired before and after chemotherapy. These patients were enrolled in the CANTO prospective study designed to record the side effects associated with the clinical management of BC. We analyzed associations between baseline or post-chemotherapy fecal microbiota and plasma metabolomics with BC prognosis, as well as with therapy-induced side effects. We examined the clinical relevance of these findings in immunocompetent mice colonized with BC patient microbiota that were subsequently challenged with histo-compatible mouse BC and chemotherapy. We conclude that specific gut commensals that are overabundant in BC patients compared with healthy individuals negatively impact BC prognosis, are modulated by chemotherapy, and may influence weight gain and neurological side effects of BC therapies. These findings obtained in adjuvant and neoadjuvant settings warrant prospective validation.

17.
Nat Commun ; 12(1): 1998, 2021 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-33790302

RESUMO

The heterogeneity of breast cancer plays a major role in drug response and resistance and has been extensively characterized at the genomic level. Here, a single-cell breast cancer mass cytometry (BCMC) panel is optimized to identify cell phenotypes and their oncogenic signalling states in a biobank of patient-derived tumour xenograft (PDTX) models representing the diversity of human breast cancer. The BCMC panel identifies 13 cellular phenotypes (11 human and 2 murine), associated with both breast cancer subtypes and specific genomic features. Pre-treatment cellular phenotypic composition is a determinant of response to anticancer therapies. Single-cell profiling also reveals drug-induced cellular phenotypic dynamics, unravelling previously unnoticed intra-tumour response diversity. The comprehensive view of the landscapes of cellular phenotypic heterogeneity in PDTXs uncovered by the BCMC panel, which is mirrored in primary human tumours, has profound implications for understanding and predicting therapy response and resistance.


Assuntos
Benzamidas/farmacologia , Neoplasias da Mama/tratamento farmacológico , Xenoenxertos/efeitos dos fármacos , Morfolinas/farmacologia , Piperazinas/farmacologia , Piridinas/farmacologia , Pirimidinas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Xenoenxertos/metabolismo , Humanos , Células MCF-7 , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Inibidores de Proteínas Quinases/farmacologia , Resultado do Tratamento
18.
NPJ Breast Cancer ; 7(1): 46, 2021 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-33893315

RESUMO

Rare protein-truncating variants (PTVs) in PALB2 confer increased risk to breast cancer, but relatively few studies have reported the characteristics of tumours with PALB2 PTVs. In this study, we describe molecular characteristics of tumours with either germline or somatic alterations in PALB2. DNA from fresh frozen tumour tissues and matched peripheral blood lymphocytes for 560 breast cancer patients was subjected for whole-exome sequencing (WES), and RNA from tumour tissues was subjected to RNA sequencing (RNA-seq). We found six cases with germline and three with somatic protein-truncating variants in PALB2. The characteristics of tumours in patients with PALB2 PTVs were similar to those with BRCA1 and BRCA2 PTVs, having significantly more somatic alterations, and a high proportion of the mutational signature and genomic scar scores characteristic of deficiencies in homologous recombination (HR), compared to tumours arising in non-carriers. Unlike tumours arising in patients with BRCA1 and BRCA2 PTVs, PALB2 tumours did not have high prevalence of TP53 somatic alterations or an enriched immune microenvironment. In summary, PALB2 tumours show the homologous recombination deficiencies characteristic of BRCA1 and BRCA2 tumours, and highlight the potential clinical relevance of PALB2 mutational status in guiding therapeutic choices.

19.
Br J Cancer ; 124(9): 1581-1591, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33723394

RESUMO

BACKGROUND: Eribulin is a microtubule-targeting agent approved for the treatment of advanced or metastatic breast cancer (BC) previously treated with anthracycline- and taxane-based regimens. PIK3CA mutation is associated with worse response to chemotherapy in oestrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic BC. We aimed to evaluate the role of phosphoinositide 3-kinase (PI3K)/AKT pathway mutations in eribulin resistance. METHODS: Resistance to eribulin was evaluated in HER2- BC cell lines and patient-derived tumour xenografts, and correlated with a mutation in the PI3K/AKT pathway. RESULTS: Eleven out of 23 HER2- BC xenografts treated with eribulin exhibited disease progression. No correlation with ER status was detected. Among the resistant models, 64% carried mutations in PIK3CA, PIK3R1 or AKT1, but only 17% among the sensitive xenografts (P = 0.036). We observed that eribulin treatment induced AKT phosphorylation in vitro and in patient tumours. In agreement, the addition of PI3K inhibitors reversed primary and acquired resistance to eribulin in xenograft models, regardless of the genetic alterations in PI3K/AKT pathway or ER status. Mechanistically, PI3K blockade reduced p21 levels likely enabling apoptosis, thus sensitising to eribulin treatment. CONCLUSIONS: PI3K pathway activation induces primary resistance or early adaptation to eribulin, supporting the combination of PI3K inhibitors and eribulin for the treatment of HER2- BC patients.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Resistencia a Medicamentos Antineoplásicos , Furanos/farmacologia , Cetonas/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor ErbB-2/metabolismo , Animais , Apoptose , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/patologia , Ciclo Celular , Proliferação de Células , Classe I de Fosfatidilinositol 3-Quinases/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Fosforilação , Proteínas Proto-Oncogênicas c-akt/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Nat Commun ; 12(1): 1502, 2021 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-33686070

RESUMO

It is unclear how genetic aberrations impact the state of nascent tumour cells and their microenvironment. BRCA1 driven triple negative breast cancer (TNBC) has been shown to arise from luminal progenitors yet little is known about how BRCA1 loss-of-function (LOF) and concomitant mutations affect the luminal progenitor cell state. Here we demonstrate how time-resolved single-cell profiling of genetically engineered mouse models before tumour formation can address this challenge. We found that perturbing Brca1/p53 in luminal progenitors induces aberrant alveolar differentiation pre-malignancy accompanied by pro-tumourigenic changes in the immune compartment. Unlike alveolar differentiation during gestation, this process is cell autonomous and characterised by the dysregulation of transcription factors driving alveologenesis. Based on our data we propose a model where Brca1/p53 LOF inadvertently promotes a differentiation program hardwired in luminal progenitors, highlighting the deterministic role of the cell-of-origin and offering a potential explanation for the tissue specificity of BRCA1 tumours.


Assuntos
Proteína BRCA1/genética , Transformação Celular Neoplásica/genética , Neoplasias Mamárias Experimentais/genética , Fenobarbital/metabolismo , Análise de Célula Única/métodos , Células-Tronco/patologia , Animais , Proteína BRCA1/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Comunicação Celular/fisiologia , Diferenciação Celular/fisiologia , Transformação Celular Neoplásica/metabolismo , Feminino , Humanos , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Mutação , Células-Tronco/fisiologia , Microambiente Tumoral/genética , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
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