92 results found
Borgoni S, Sofyali E, Soleimani M, et al., 2020, Time-Resolved Profiling Reveals ATF3 as a Novel Mediator of Endocrine Resistance in Breast Cancer, CANCERS, Vol: 12
Borgoni S, Sofyalı E, Soleimani M, et al., 2020, Time-resolved profiling reveals ATF3 as a novel mediator of endocrine resistance in breast cancer
<jats:title>Abstract</jats:title><jats:p>Breast cancer is one of the leading causes of death for women worldwide. Patients whose tumors express Estrogen Receptor α (ERα) account for around 70% of cases and are mostly treated with targeted endocrine therapy. However, 40% of these tumors eventually relapse due to resistance development and further treatment of these patients is highly ineffective. In this study we profiled the early phases of the resistance development process to uncover drivers of this phenomenon. Time-resolved analysis revealed that ATF3, a member of the ATF/CREB family of transcription factors, acts as a novel regulator of the response to therapy via rewiring of central signaling processes towards the adaptation to endocrine treatment. ATF3 was found to be essential in controlling crucial processes such as proliferation, cell cycle and apoptosis during the early response to treatment through the regulation of MAPK/AKT signaling pathways. Its essential role was confirmed <jats:italic>in vivo</jats:italic> in a mouse model and elevated expression of ATF3 was verified in patient datasets, adding clinical relevance to our findings. This study proposes ATF3 as a novel mediator of endocrine resistance development in breast cancer and elucidates its role in the regulation of downstream pathways activities.</jats:p>
Tsolaki E, Doran W, Magnani L, et al., 2020, Invasive breast tumors are characterized by the presence of crystalline nanoparticles
<jats:p>The presence of calcification in tumours has been known for decades<jats:sup>1</jats:sup>. Indeed, calcified breast tissue is a fundamental criterion for early breast cancer diagnosis, indicative of malignancies<jats:sup>2</jats:sup>, and their appearance is used to distinguish between benign and malignant in breast biopsies<jats:sup>3,4</jats:sup>. However, an in-depth characterization of the nature and origin of tumour tissue calcification remains elusive<jats:sup>5–8</jats:sup>. Here, we report the presence of nano and micron-sized spherical particles made of highly crystalline whitlockite that are exclusively found in the arterial wall of malignant invasive tumours. By applying nanoanalytical methods to healthy, benign and malignant tumour breast tissue biopsies from patients, we show that poorly crystalline apatite can be found in all breast tissue samples, whereas spherical crystalline whitlockite particles are present only in invasive cancers, mainly in areas close to the lumen of the arterial wall. Moreover, we demonstrate that the concentration of these spherical crystalline particles increases with the grade of disease, and that their size can be related to tumour type. Therefore, our results not only provide new insight into calcification of tumour tissue, but also enable a precise, yet simple route of breast cancer diagnosis and staging.</jats:p>
Acar A, Nichol D, Fernandez-Mateos J, et al., 2020, Exploiting evolutionary steering to induce collateral drug sensitivity in cancer, Nature Communications, Vol: 11, Pages: 1-14, ISSN: 2041-1723
Drug resistance mediated by clonal evolution is arguably the biggest problem in cancer therapy today. However, evolving resistance to one drug may come at a cost of decreased fecundity or increased sensitivity to another drug. These evolutionary trade-offs can be exploited using ‘evolutionary steering’ to control the tumour population and delay resistance. However, recapitulating cancer evolutionary dynamics experimentally remains challenging. Here, we present an approach for evolutionary steering based on a combination of single-cell barcoding, large populations of 108–109 cells grown without re-plating, longitudinal non-destructive monitoring of cancer clones, and mathematical modelling of tumour evolution. We demonstrate evolutionary steering in a lung cancer model, showing that it shifts the clonal composition of the tumour in our favour, leading to collateral sensitivity and proliferative costs. Genomic profiling revealed some of the mechanisms that drive evolved sensitivity. This approach allows modelling evolutionary steering strategies that can potentially control treatment resistance.
Cresswell GD, Nichol D, Spiteri I, et al., 2020, Mapping the breast cancer metastatic cascade onto ctDNA using genetic and epigenetic clonal tracking, Nature Communications, Vol: 11, Pages: 1-12, ISSN: 2041-1723
Circulating tumour DNA (ctDNA) allows tracking of the evolution of human cancers at high resolution, overcoming many limitations of tissue biopsies. However, exploiting ctDNA to determine how a patient’s cancer is evolving in order to aid clinical decisions remains difficult. This is because ctDNA is a mix of fragmented alleles, and the contribution of different cancer deposits to ctDNA is largely unknown. Profiling ctDNA almost invariably requires prior knowledge of what genomic alterations to track. Here, we leverage on a rapid autopsy programme to demonstrate that unbiased genomic characterisation of several metastatic sites and concomitant ctDNA profiling at whole-genome resolution reveals the extent to which ctDNA is representative of widespread disease. We also present a methylation profiling method that allows tracking evolutionary changes in ctDNA at single-molecule resolution without prior knowledge. These results have critical implications for the use of liquid biopsies to monitor cancer evolution in humans and guide treatment.
Coleman I, Corleone G, Arram J, et al., 2020, GeDi: applying su x arrays to increase the repertoire of detectable SNVs in tumour genomes, BMC Bioinformatics, Vol: 21, ISSN: 1471-2105
BackgroundCurrent popular variant calling pipelines rely on the mapping coordinates of each input read to a reference genome in order to detect variants. Since reads deriving from variant loci that diverge in sequence substantially from the reference are often assigned incorrect mapping coordinates, variant calling pipelines that rely on mapping coordinates can exhibit reduced sensitivity.ResultsIn this work we present GeDi, a suffix array-based somatic single nucleotide variant (SNV) calling algorithm that does not rely on read mapping coordinates to detect SNVs and is therefore capable of reference-free and mapping-free SNV detection. GeDi executes with practical runtime and memory resource requirements, is capable of SNV detection at very low allele frequency (<1%), and detects SNVs with high sensitivity at complex variant loci, dramatically outperforming MuTect, a well-established pipeline.ConclusionBy designing novel suffix-array based SNV calling methods, we have developed a practical SNV calling software, GeDi, that can characterise SNVs at complex variant loci and at low allele frequency thus increasing the repertoire of detectable SNVs in tumour genomes. We expect GeDi to find use cases in targeted-deep sequencing analysis, and to serve as a replacement and improvement over previous suffix-array based SNV calling methods.
Rocca A, Ravaioli S, Fonzi E, et al., 2020, Breast cancer subtype classification using NanoString and RNAseq technologies, San Antonio Breast Cancer Symposium, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Magnani L, Barozzi I, Hong S, 2020, Single cell transcriptomics reveals multi-step adaptations to endocrine therapy, San Antonio Breast Cancer Symposium, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Zoppoli G, Garuti A, Belfiore A, et al., 2020, Ultra-deep multigene profiling of matched primary and metastatic hormone receptor positive breast cancer patients relapsed after adjuvant endocrine treatment reveals novel aberrations in the estrogen receptor pathway, San Antonio Breast Cancer Symposium, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Mensa E, Guescini M, Giuliani A, et al., 2020, Small extracellular vesicles deliver miR-21 and miR-217 as pro-senescence effectors to endothelial cells, JOURNAL OF EXTRACELLULAR VESICLES, Vol: 9
Zhang Y, Takahashi Y, Hong SP, et al., 2019, High-resolution label-free 3D mapping of extracellular pH of single living cells, Nature Communications, Vol: 10, ISSN: 2041-1723
Dynamic mapping of extracellular pH (pHe) at the single-cell level is critical for understanding the role of H+ in cellular and subcellular processes, with particular importance in cancer. While several pHe sensing techniques have been developed, accessing this information at the single-cell level requires improvement in sensitivity, spatial and temporal resolution. We report on a zwitterionic label-free pH nanoprobe that addresses these long-standing challenges. The probe has a sensitivity >0.01 units, 2 ms response time, and 50 nm spatial resolution. The technology was incorporated into a double-barrel nanoprobe integrating pH sensing with feedback-controlled distance sensing via Scanning Ion Conductance Microscopy. This allows for the simultaneous 3D topographical imaging and pHe monitoring of living cancer cells. These classes of nanoprobes were used for real-time high spatiotemporal resolution pHe mapping at the subcellular level and revealed tumour heterogeneity of the peri-cellular environments of melanoma and breast cancer cells.
Trasanidis N, Katsarou A, Bergonia B, et al., 2019, PBX1 Co-Operates with FOXM1 to Regulate Myeloma Cell Proliferation and to Define an Ultra High-Risk chr1q Gain Myeloma Patient Subgroup, BLOOD, Vol: 134, ISSN: 0006-4971
Hong SP, Lombardo Y, Chan TE, et al., 2019, Single-cell transcriptomics reveals multi-step adaptations to endocrine therapy, Nature Communications, Vol: 10, ISSN: 2041-1723
Resistant tumours are thought to arise from the action of Darwinian selection on genetically heterogenous cancer cell populations. However, simple clonal selection is inadequate to describe the late relapses often characterising luminal breast cancers treated with endocrine therapy (ET), suggesting a more complex interplay between genetic and non-genetic factors. Here, we dissect the contributions of clonal genetic diversity and transcriptional plasticity during the early and late phases of ET at single-cell resolution. Using single-cell RNA-sequencing and imaging we disentangle the transcriptional variability of plastic cells and define a rare sub population of pre-adapted (PA) cells which undergoes further transcriptomic reprogramming and copy number changes to acquire full resistance. We find evidence for sub-clonal expression of a PA signature in primary tumours and for dominant expression in clustered circulating tumour cells. We propose a multi-step model for ET resistance development and advocate the use of stage-specific biomarkers.
Perone Y, Farrugia AJ, Rodriguez-Meira A, et al., 2019, SREBP1 drives keratin-80-dependent cytoskeletal changes and invasive behavior in endocrine-resistant ER alpha breast cancer (vol 10, 2115, 2019), NATURE COMMUNICATIONS, Vol: 10, ISSN: 2041-1723
Ottaviani S, Stebbing J, Frampton AE, et al., 2019, Author Correction: TGF-beta induces miR-100 and miR-125b but blocks let-7a through LIN28B controlling PDAC progression, Nature Communications, Vol: 10, ISSN: 2041-1723
Nguyen VTM, Barozzi I, Faronato M, et al., 2019, Author Correction: Differential epigenetic reprogramming in response to specific endocrine therapies promotes cholesterol biosynthesis and cellular invasion, Nature Communications, Vol: 10, ISSN: 2041-1723
Perone Y, Farrugia AJ, Meira AR, et al., 2019, SREBP1 drives Keratin 80-dependent cytoskeletal changes and invasive behavior in endocrine resistant ERα breast cancer, Nature Communications, Vol: 10, ISSN: 2041-1723
Approximately 30% of ERα breast cancer patients relapse with metastatic disease following adjuvant endocrine therapies. The connection between acquisition of drug resistance and invasive potential is poorly understood. In this study, we demonstrate that the type II keratin topological associating domain undergoes epigenetic reprogramming in aromatase inhibitors (AI)-resistant cells, leading to Keratin-80 (KRT80) upregulation. KRT80 expression is driven by de novo enhancer activation by sterol regulatory element-binding protein 1 (SREBP1). KRT80 upregulation directly promotes cytoskeletal rearrangements at the leading edge, increased focal adhesion and cellular stiffening, collectively promoting cancer cell invasion. Shearwave elasticity imaging performed on prospectively recruited patients confirms KRT80 levels correlate with stiffer tumors. Immunohistochemistry showed increased KRT80-positive cells at relapse and, using several clinical endpoints, KRT80 expression associates with poor survival. Collectively, our data uncover an unpredicted and potentially targetable direct link between epigenetic and cytoskeletal reprogramming promoting cell invasion in response to chronic AI treatment.
Perone Y, Rodríguez Meira A, Farruggia A, et al., 2019, OR34-2 SREBP1 Drives KRT80-Dependent Cytoskeletal Changes and Invasive Behaviour in Endocrine-Resistant ERα Breast Cancer, Journal of the Endocrine Society, Vol: 3
Acar A, Nichol D, Fernandez-Mateos J, et al., 2019, Exploiting evolutionary herding to control drug resistance in cancer
<jats:title>Abstract</jats:title><jats:p>Drug resistance mediated by clonal evolution is arguably the biggest problem in cancer therapy today. However, evolving resistance to one drug may come at a cost of decreased growth rate or increased sensitivity to another drug due to evolutionary trade-offs. This weakness can be exploited in the clinic using an approach called ‘evolutionary herding’ that aims at controlling the tumour cell population to delay or prevent resistance. However, recapitulating cancer evolutionary dynamics experimentally remains challenging. Here we present a novel approach for evolutionary herding based on a combination of single-cell barcoding, very large populations of 10<jats:sup>8</jats:sup>–10<jats:sup>9</jats:sup>cells grown without re-plating, longitudinal non-destructive monitoring of cancer clones, and mathematical modelling of tumour evolution. We demonstrate evolutionary herding in non-small cell lung cancer, showing that herding allows shifting the clonal composition of a tumour in our favour, leading to collateral drug sensitivity and proliferative fitness costs. Through genomic analysis and single-cell sequencing, we were also able to determine the mechanisms that drive such evolved sensitivity. Our approach allows modelling evolutionary trade-offs experimentally to test patient-specific evolutionary herding strategies that can potentially be translated into the clinic to control treatment resistance.</jats:p>
Varghese V, Magnani L, Harada N, et al., 2019, FOXM1 modulates 5-FU resistance in colorectal cancer through regulating TYMS expression, Scientific Reports, Vol: 9, ISSN: 2045-2322
Resistance to 5-Fluoruracil (5-FU) has been linked to elevated expression of the main target, thymidylate synthase (TYMS), which catalyses the de novo pathway for production of deoxythymidine monophosphate. The potent oncogenic forkhead box transcription factor, FOXM1 is is regulated by E2F1 which also controls TYMS. This study reveals a significant role of FOXM1 in 5-FU resistance. Overexpression and knock-down studies of FOXM1 in colon cancer cells suggest the importance of FOXM1 in TYMS regulation. ChIP and global ChIP-seq data also confirms that FOXM1 can also potentially regulate other 5-FU targets, such as TYMS, thymidine kinase 1 (TK-1) and thymidine phosphorylase (TYMP). In human colorectal cancer tissue specimens, a strong correlation of FOXM1 and TYMS staining was observed. Elevated FOXM1 and TYMS expression was also observed in acquired 5-FU resistant colon cancer cells (HCT116 5-FU Res). A synergistic effect was observed following treatment of CRC cells with an inhibitor of FOXM1, thiostrepton, in combination with 5-FU. The combination treatment decreased colony formation and migration, and induced cell cycle arrest, DNA damage, and apoptosis in CRC cell lines. In summary, this research demonstrated that FOXM1 plays a pivotal role in 5-FU resistance at least partially through the regulation of TYMS.
Ferrari N, Ranftl R, Chicherova I, et al., 2019, Dickkopf-3 links HSF1 and YAP/TAZ signalling to control aggressive behaviours in cancer-associated fibroblasts, Nature Communications, Vol: 10, ISSN: 2041-1723
Aggressive behaviours of solid tumours are highly influenced by the tumour microenvironment. Multiple signalling pathways can affect the normal function of stromal fibroblasts in tumours, but how these events are coordinated to generate tumour-promoting cancer-associated fibroblasts (CAFs) is not well understood. Here we show that stromal expression of Dickkopf-3 (DKK3) is associated with aggressive breast, colorectal and ovarian cancers. We demonstrate that DKK3 is a HSF1 effector that modulates the pro-tumorigenic behaviour of CAFs in vitro and in vivo. DKK3 orchestrates a concomitant activation of β-catenin and YAP/TAZ. Whereas β-catenin is dispensable for CAF-mediated ECM remodelling, cancer cell growth and invasion, DKK3-driven YAP/TAZ activation is required to induce tumour-promoting phenotypes. Mechanistically, DKK3 in CAFs acts via canonical Wnt signalling by interfering with the negative regulator Kremen and increasing cell-surface levels of LRP6. This work reveals an unpredicted link between HSF1, Wnt signalling and YAP/TAZ relevant for the generation of tumour-promoting CAFs.
Hong SP, Chan TE, Lombardo Y, et al., 2018, Single-cell Transcriptomics reveals multi-step adaptations to endocrine therapy
<jats:title>Abstract</jats:title><jats:p>Resistant tumours are thought to arise from the action of Darwinian selection on genetically heterogenous cancer cell populations. However, simple clonal selection is inadequate to describe the late relapses often characterising luminal breast cancers treated with endocrine therapy (ET), suggesting a more complex interplay between genetic and non-genetic factors. Partially, this is due to our limited understanding on the effect of ET at the single cell level. In the present study, we dissect the contributions of clonal genetic diversity and transcriptional plasticity during the early and late phases of ET at single-cell resolution. Using single-cell RNA-sequencing and imaging we disentangle the transcriptional variability of plastic cells and define a rare sub-population of pre-adapted (PA) cells which undergoes further transcriptomic reprogramming and copy number changes to acquire full resistance. PA cells show reduced oestrogen receptor α activity but increased features of quiescence and migration. We find evidence for sub-clonal expression of this PA signature in primary tumours and for dominant expression in clustered circulating tumour cells. We propose a multi-step model for ET resistance development and advocate the use of stage-specific biomarkers.</jats:p>
Perone Y, Farrugia AJ, Meira AR, et al., 2018, SREBP1 drives KRT80-dependent cytoskeletal changes and invasive behavior in endocrine resistant ERα breast cancer
<jats:title>Abstract</jats:title><jats:p>Approximately 30% of women diagnosed with ERα breast cancer relapse with metastatic disease following adjuvant treatment with endocrine therapies<jats:sup>1,2</jats:sup>. The connection between acquisition of drug resistance and invasive potential is poorly understood. In this study, we demonstrate that the type II keratin topological associating domain (TAD)<jats:sup>3</jats:sup> undergoes epigenetic reprogramming in cells that develop resistance to aromatase inhibitors (AI), leading to keratin 80 (KRT80) upregulation. In agreement, an increased number of KRT80-positive cells are observed at relapse <jats:italic>in vivo</jats:italic> while KRT80 expression associates with poor outcome using several clinical endpoints. KRT80 expression is driven by <jats:italic>de novo</jats:italic> enhancer activation by sterol regulatory element-binding protein 1<jats:sup>4</jats:sup> (SREBP1). KRT80 upregulation directly promotes cytoskeletal rearrangements at the leading edge, increased focal adhesion maturation and cellular stiffening, which collectively promote cancer cell invasion. Shear-wave elasticity imaging of prospective patients shows that KRT80 levels correlate with stiffer tumors <jats:italic>in vivo</jats:italic>. Collectively, our data uncover an unpredicted and potentially targetable direct link between epigenetic and cytoskeletal reprogramming promoting cell invasion in response to chronic AI treatment.</jats:p>
Patten DK, Corleone G, Győrffy B, et al., 2018, Enhancers mapping uncovers phenotypic heterogeneity and evolution in patients with luminal breast cancer, Nature Medicine, Vol: 24, Pages: 1469-1480, ISSN: 1078-8956
The degree of intrinsic and interpatient phenotypic heterogeneity and its role in tumor evolution is poorly understood. Phenotypic drifts can be transmitted via inheritable transcriptional programs. Cell-type specific transcription is maintained through the activation of epigenetically defined regulatory regions including promoters and enhancers. Here we have annotated the epigenome of 47 primary and metastatic estrogen-receptor (ERα)-positive breast cancer clinical specimens and inferred phenotypic heterogeneity from the regulatory landscape, identifying key regulatory elements commonly shared across patients. Shared regions contain a unique set of regulatory information including the motif for transcription factor YY1. We identify YY1 as a critical determinant of ERα transcriptional activity promoting tumor growth in most luminal patients. YY1 also contributes to the expression of genes mediating resistance to endocrine treatment. Finally, we used H3K27ac levels at active enhancer elements as a surrogate of intra-tumor phenotypic heterogeneity to track the expansion and contraction of phenotypic subpopulations throughout breast cancer progression. By tracking the clonality of SLC9A3R1-positive cells, a bona fide YY1-ERα-regulated gene, we show that endocrine therapies select for phenotypic clones under-represented at diagnosis. Collectively, our data show that epigenetic mechanisms significantly contribute to phenotypic heterogeneity and evolution in systemically treated breast cancer patients.
Ottaviani S, Stebbing J, Frampton AE, et al., 2018, TGF-beta induces miR-100 and miR-125b but blocks let-7a through LIN28B controlling PDAC progression, Nature Communications, Vol: 9, ISSN: 2041-1723
TGF-β/Activin induces epithelial-to-mesenchymal transition and stemness in pancreatic ductal adenocarcinoma (PDAC). However, the microRNAs (miRNAs) regulated during this response have remained yet undetermined. Here, we show that TGF-β transcriptionally induces MIR100HG lncRNA, containing miR-100, miR-125b and let-7a in its intron, via SMAD2/3. Interestingly, we find that although the pro-tumourigenic miR-100 and miR-125b accordingly increase, the amount of anti-tumourigenic let-7a is unchanged, as TGF-β also induces LIN28B inhibiting its maturation. Notably, we demonstrate that inactivation of miR-125b or miR-100 affects the TGF-β-mediated response indicating that these miRNAs are important TGF-β effectors. We integrate AGO2-RIP-seq with RNA-seq to identify the global regulation exerted by these miRNAs in PDAC cells. Transcripts targeted by miR-125b and miR-100 significantly overlap and mainly inhibit p53 and cell–cell junctions’ pathways. Together, we uncover that TGF-β induces an lncRNA, whose encoded miRNAs, miR-100, let-7a and miR-125b play opposing roles in controlling PDAC tumourigenesis.
Noberini R, Osti D, Miccolo C, et al., 2018, Extensive and systematic rewiring of histone post-translational modifications in cancer model systems, Nucleic Acids Research, Vol: 46, Pages: 3817-3832, ISSN: 0305-1048
Histone post-translational modifications (PTMs) generate a complex combinatorial code that regulates gene expression and nuclear functions, and whose deregulation has been documented in different types of cancers. Therefore, the availability of relevant culture models that can be manipulated and that retain the epigenetic features of the tissue of origin is absolutely crucial for studying the epigenetic mechanisms underlying cancer and testing epigenetic drugs. In this study, we took advantage of quantitative mass spectrometry to comprehensively profile histone PTMs in patient tumor tissues, primary cultures and cell lines from three representative tumor models, breast cancer, glioblastoma and ovarian cancer, revealing an extensive and systematic rewiring of histone marks in cell culture conditions, which includes a decrease of H3K27me2/me3, H3K79me1/me2 and H3K9ac/K14ac, and an increase of H3K36me1/me2. While some changes occur in short-term primary cultures, most of them are instead time-dependent and appear only in long-term cultures. Remarkably, such changes mostly revert in cell line- and primary cell-derived in vivo xenograft models. Taken together, these results support the use of xenografts as the most representative models of in vivo epigenetic processes, suggesting caution when using cultured cells, in particular cell lines and long-term primary cultures, for epigenetic investigations.
Patten DK, Corleone G, Győrffy B, et al., 2017, Enhancers mapping uncovers phenotypic heterogeneity and evolution in patients with luminal breast cancer
<jats:title>Abstract</jats:title><jats:p>The degree of intrinsic and interpatient phenotypic heterogeneity and its role in tumour evolution is poorly understood. Phenotypic divergence can be achieved via the inheritance of alternative transcriptional programs<jats:sup>1,2</jats:sup>. Cell-type specific transcription is maintained through the activation of epigenetically-defined regulatory regions including promoters and enhancers<jats:sup>1,3,4</jats:sup>. In this work, we annotated the epigenome of 47 primary and metastatic oestrogen-receptor (ERα)-positive breast cancer specimens from clinical samples, and developed strategies to deduce phenotypic heterogeneity from the regulatory landscape, identifying key regulatory elements commonly shared across patients. Highly shared regions contain a unique set of regulatory information including the motif for the transcription factor YY1. <jats:italic>In vitro</jats:italic> work shows that YY1 is essential for ERα transcriptional activity and defines the critical subset of functional ERα binding sites driving tumor growth in most luminal patients. YY1 also control the expression of genes that mediate resistance to endocrine treatment. Finally, we show that H3K27ac levels at active enhancer elements can be used as a surrogate of intra-tumor phenotypic heterogeneity, and to track expansion and contraction of phenotypic subpopulations throughout breast cancer progression. Tracking YY1 and SLC9A3R1 positive clones in primary and metastatic lesions, we show that endocrine therapies drive the expansion of phenotypic clones originally underrepresented at diagnosis. Collectively, our data show that epigenetic mechanisms significantly contribute to phenotypic heterogeneity and evolution in systemically treated breast cancer patients.</jats:p>
Magnani L, Frige G, Gadaleta RM, et al., 2017, Corrigendum: Acquired CYP19A1 amplification is an early specific mechanism of aromatase inhibitor resistance in ER alpha metastatic breast cancer, Nature Genetics, Vol: 49, Pages: 970-970, ISSN: 1061-4036
Magnani L, Frige G, Gadaleta RM, et al., 2017, Acquired CYP19A1 amplification is an early specific mechanism of aromatase inhibitor resistance in ERα metastatic breast cancer, Nature Genetics, Vol: 49, Pages: 444-450, ISSN: 1546-1718
Tumor evolution is shaped by many variables, potentially involving external selective pressures induced by therapies1. After surgery, estrogen receptor (ERα) positive breast cancer (BCa) patients are treated with adjuvant endocrine therapy2including selective estrogen receptor modulators (SERMs) and/or aromatase inhibitors (AIs)3. However, over 20% of patients relapse within 10 years and eventually progress to incurable metastatic disease4. Here we demonstratethat the choice of therapy has a fundamental influence on the genetic landscape of relapsed diseases: in this study, 21.5% of AI-treated, relapsed patients had acquiredCYP19A1gene (aromatase) amplification (CYP19A1amp). Relapsed patients also developed numerous mutations targeting key breast cancer genes including ESR1 and CYP19A1. Strikingly, CYP19A1amp cells also emerge in vitrobut only in AI resistant models. CYP19A1 amplification causesincreased aromatase activity and estrogen-independent ERα binding to target genesresulting inCYP19A1amp cells displaying decreased sensitivity to AI treatment. Collectively these data suggest that AI treatment itself selects for acquiredCYP19A1 amplification and promotes local autocrine estrogen signalling in AI resistant metastatic patients.
Magnani L, Patten DK, 2017, Fundamental pathways in breast cancer 3: Estrogen biology, Breast Cancer: Innovations in Research and Management, Pages: 19-26, ISBN: 9783319488462
© Springer International Publishing AG 2017. Over the last two decades, it has become evident that breast cancer should be considered as a family of diseases rather than as a unique malignancy. Pathological, molecular, and genetic analysis have revealed the existence of five to ten main subgroups [1-3]. Over 70% of all patients are generally classified by the tumor dependencies on estrogenic compounds . These dependencies are principally mediated by the nuclear receptor estrogen receptor a (ERa) [5, 6]. For all these reasons, ERa remains the key driver in the majority of breast cancers and is commonly used as a molecular biomarker for stratification while serving as the main target for systemic adjuvant chemotherapy. In this chapter I will discuss the molecular mechanisms of ERa activation focusing on integrative analysis that have recently exposed the intimate link between ERa and chromatin structure.
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