scholarly journals Subtype-Independent ANP32E Reduction During Breast Cancer Progression in Accordance with Chromatin Relaxation

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Garrett L. Ruff ◽  
Kristin E. Murphy ◽  
Zachary R. Smith ◽  
Paula M. Vertino ◽  
Patrick J. Murphy
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Tumor Biology ◽  
Gene Expression Signature ◽  
State Regulation ◽  
Chromatin State ◽  
Stable Form ◽  
Hormone Receptor Positive ◽  
Tumor Plasticity ◽  
Genomic Studies

Abstract Background Chromatin state provides a clear decipherable blueprint for maintenance of transcriptional patterns, exemplifying a mitotically stable form of cellular programming in dividing cells. In this regard, genomic studies of chromatin states within cancerous tissues have the potential to uncover novel aspects of tumor biology and unique mechanisms associated with disease phenotypes and outcomes. The degree to which chromatin state differences occur in accordance with breast cancer features has not been established. Methods We applied a series of unsupervised computational methods to identify chromatin and molecular differences associated with discrete physiologies across human breast cancer tumors. Results Chromatin patterns alone are capable of stratifying tumors in association with cancer subtype and disease progression. Major differences occur at DNA motifs for the transcription factor FOXA1, in hormone receptor-positive tumors, and motifs for SOX9 in Basal-like tumors. We find that one potential driver of this effect, the histone chaperone ANP32E, is inversely correlated with tumor progression and relaxation of chromatin at FOXA1 binding sites. Tumors with high levels of ANP32E exhibit an immune response and proliferative gene expression signature, whereas tumors with low ANP32E levels appear programmed for differentiation. Conclusions Our results indicate that ANP32E may function through chromatin state regulation to control breast cancer differentiation and tumor plasticity. This study sets a precedent for future computational studies of chromatin changes in carcinogenesis.

scholarly journals Chromatin Patterns Distinguish Breast Tumor Subtypes and Disease Progression in Association with ANP32E levels

2021 ◽  
Author(s):  
Garrett L Ruff ◽  
Kristin E Murphy ◽  
Paula M Vertino ◽  
Patrick J Murphy
Keyword(s):  
Breast Cancer ◽  
Treatment Strategies ◽  
Gene Expression Signature ◽  
Chromatin Accessibility ◽  
State Regulation ◽  
Molecular Characteristics ◽  
Luminal A ◽  
Chromatin Signature ◽  
Tumor Plasticity ◽  
Chromatin Patterns

Despite highly advanced diagnosis and treatment strategies, breast cancer patient outcomes vary extensively, even among individuals with the same diagnosis. Thus, a better understanding of the unique molecular characteristics that underlie tumor trajectories and responses to therapy remains a central goal. We report that chromatin patterns represent an important characteristic, capable of stratifying tumor identity and progression. We find that patterns of chromatin accessibility can be classified into 3 major groups, representing Basal-like tumors, hormone receptor (HR)-expressing tumors, and invasive lobular Luminal-A tumors. Major chromatin differences occur throughout the genome at motifs for the transcription factor FOXA1 in HR-positive tumors, and motifs for SOX9 in Basal-like tumors. A large portion of lobular Luminal-A tumors display a chromatin signature defined by accessibility at FOXA1 binding motifs, distinguishing them from others within this subtype. Expression of the histone chaperone ANP32E is inversely correlated with tumor progression and chromatin accessibility at FOXA1 binding sites. Tumors with high levels of ANP32E exhibit an immune response and proliferative gene expression signature, whereas tumors with low ANP32E levels appear programmed for differentiation. Our results indicate that ANP32E may function through chromatin state regulation to control breast cancer differentiation and tumor plasticity.

scholarly journals Immune microenvironment and intrinsic subtyping in hormone receptor-positive/HER2-negative breast cancer

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Gaia Griguolo ◽  
Maria Vittoria Dieci ◽  
Laia Paré ◽  
Federica Miglietta ◽  
Daniele Giulio Generali ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Gene Expression Data ◽  
Hormone Receptor ◽  
Tumor Biology ◽  
Expression Data ◽  
Immune Microenvironment ◽  
Immune Infiltrate ◽  
Hormone Receptor Positive ◽  
Her2 Breast Cancer

AbstractLittle is known regarding the interaction between immune microenvironment and tumor biology in hormone receptor (HR)+/HER2− breast cancer (BC). We here assess pretreatment gene-expression data from 66 HR+/HER2− early BCs from the LETLOB trial and show that non-luminal tumors (HER2-enriched, Basal-like) present higher tumor-infiltrating lymphocyte levels than luminal tumors. Moreover, significant differences in immune infiltrate composition, assessed by CIBERSORT, were observed: non-luminal tumors showed a more proinflammatory antitumor immune infiltrate composition than luminal ones.

scholarly journals Role of the NUDT Enzymes in Breast Cancer

2021 ◽  
Vol 22 (5) ◽  
pp. 2267
Author(s):  
Roni H. G. Wright ◽  
Miguel Beato
Keyword(s):  
Breast Cancer ◽  
Signaling Pathways ◽  
Cancer Progression ◽  
Breast Cancers ◽  
Metastatic Colonization ◽  
Hormone Receptor Positive ◽  
Aggressive Cancer ◽  
Cancer Types ◽  
Metastatic Process

Despite global research efforts, breast cancer remains the leading cause of cancer death in women worldwide. The majority of these deaths are due to metastasis occurring years after the initial treatment of the primary tumor and occurs at a higher frequency in hormone receptor-positive (Estrogen and Progesterone; HR+) breast cancers. We have previously described the role of NUDT5 (Nudix-linked to moiety X-5) in HR+ breast cancer progression, specifically with regards to the growth of breast cancer stem cells (BCSCs). BCSCs are known to be the initiators of epithelial-to-mesenchyme transition (EMT), metastatic colonization, and growth. Therefore, a greater understanding of the proteins and signaling pathways involved in the metastatic process may open the door for therapeutic opportunities. In this review, we discuss the role of NUDT5 and other members of the NUDT family of enzymes in breast and other cancer types. We highlight the use of global omics data based on our recent phosphoproteomic analysis of progestin signaling pathways in breast cancer cells and how this experimental approach provides insight into novel crosstalk mechanisms for stratification and drug discovery projects aiming to treat patients with aggressive cancer.

scholarly journals PPARgamma: A Potential Intrinsic and Extrinsic Molecular Target for Breast Cancer Therapy

Biomedicines ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 543
Author(s):  
Giuseppina Augimeri ◽  
Daniela Bonofiglio
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Cancer Progression ◽  
Regulatory Networks ◽  
Tumor Biology ◽  
Peroxisome Proliferator ◽  
Breast Cancer Patients ◽  
Peroxisome Proliferator Activated Receptor ◽  
Extracellular Matrix Components

Over the last decades, the breast tumor microenvironment (TME) has been increasingly recognized as a key player in tumor development and progression and as a promising prognostic and therapeutic target for breast cancer patients. The breast TME, representing a complex network of cellular signaling—deriving from different stromal cell types as well as extracellular matrix components, extracellular vesicles, and soluble growth factors—establishes a crosstalk with cancer cells sustaining tumor progression. A significant emphasis derives from the tumor surrounding inflammation responsible for the failure of the immune system to effectively restrain breast cancer growth. Thus, effective therapeutic strategies require a deeper understanding of the interplay between tumor and stroma, aimed at targeting both the intrinsic neoplastic cells and the extrinsic surrounding stroma. In this scenario, peroxisome proliferator-activated receptor (PPAR) γ, primarily known as a metabolic regulator, emerged as a potential target for breast cancer treatment since it functions in breast cancer cells and several components of the breast TME. In particular, the activation of PPARγ by natural and synthetic ligands inhibits breast cancer cell growth, motility, and invasiveness. Moreover, activated PPARγ may educate altered stromal cells, counteracting the pro-inflammatory milieu that drive breast cancer progression. Interestingly, using Kaplan–Meier survival curves, PPARγ also emerges as a prognostically favorable factor in breast cancer patients. In this perspective, we briefly discuss the mechanisms by which PPARγ is implicated in tumor biology as well as in the complex regulatory networks within the breast TME. This may help to profile approaches that provide a simultaneous inhibition of epithelial cells and TME components, offering a more efficient way to treat breast cancer.

scholarly journals Prediction of Survival after Eribulin Chemotherapy for Breast Cancer by Absolute Lymphocyte Counts and Progression Types

2020 ◽  
Author(s):  
Tamami Morisaki ◽  
Shinichiro Kashiwagi ◽  
Yuka Asano ◽  
Wataru Goto ◽  
Koji Takada ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Immune Response ◽  
Cancer Progression ◽  
Locally Advanced ◽  
Tumor Biology ◽  
Metastatic Breast ◽  
The Other ◽  
Other Hand ◽  
Significant Difference ◽  
Absolute Lymphocyte Counts

Abstract Background: In the RECIST diagnostic criteria, the concepts of progression by pre-existing disease (PPL) and progression by new metastases (PNM) have been proposed to distinguish between the progression types of cancer refractory to treatment. According to the tumor biology of cancer progression forms, the "PPL" form indicates invasion and the "PNM" form indicates metastasis. On the other hand, recent studies have focused on the clinical importance of inflammatory markers as indicators of the systemic tumor immune response. In particular, absolute lymphocyte counts (ALC) is an indicator of the host’s immune response. Thus, we developed a new measure that combined progression form with ALC. In this study, we clinically validated the combined assessment of progression form and ALC in eribulin chemotherapy.Methods: From August 2011 to April 2019, a total of 486 patients with locally advanced or metastatic breast cancer (MBC) underwent treatment. In this study, only 88 patients who underwent chemotherapy using eribulin were included. The antitumor effect was evaluated based on the RECIST criteria, version 1.1. To measure ALC, peripheral blood samples collected before eribulin treatment were used. The cut-off value for ALC in this study was 1,500 /μL, based on previous studies.Results: The PPL group (71 patients, 80.7%) had significantly longer PFS (p=0.022, log-rank) and OS (p<0.001, log-rank) than the PNM group (17 patients,19.3%). In the 51 patients with ALC <1500/μl, the PPL group had a significantly better prognosis than the PNM group (PFS: p=0.035, OS: p<0.001, log-rank, respectively). On the other hand, in the 37 patients with ALC≥1500/μl, the PPL group had a better OS compared to the PNM group (p=0.055, log-rank), but there was no significant difference in PFS between the two groups (p=0.541, log-rank). Furthermore, multivariate analysis that validated the effect of OS showed that high ORR and “high-ALC and PPL” were factors for a good prognosis (p<0.001, HR=0.321) (p=0.036, HR=0.290).Conclusions: In breast cancer patients with eribulin chemotherapy, good systemic immune status, such as ALC≥1500/μl, was associated with less progression, particularly metastasis, and better prognosis. Furthermore, the biomarker "high-ALC and PPL" was particularly useful as a prognostic marker following eribulin chemotherapy.

scholarly journals Prognostic Value of CXCR2 in Breast Cancer

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2076
Author(s):  
Florence Boissière-Michot ◽  
William Jacot ◽  
Julien Fraisse ◽  
Sophie Gourgou ◽  
Colin Timaxian ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Stromal Cells ◽  
Lower Risk ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Hormone Receptor Positive ◽  
Chemokine Receptor Cxcr2 ◽  
Risk Of Relapse

The tumor microenvironment appears essential in cancer progression and chemokines are mediators of the communication between cancer cells and stromal cells. We have previously shown that the ligands of the chemokine receptor CXCR2 were expressed at higher levels in triple-negative breast cancers (TNBC). Our hypothesis was that CXCR2 expression could also be altered in breast cancer. Here, we have analyzed the potential role of CXCR2 in breast cancer in a retrospective cohort of 105 breast cancer patients. Expression of CXCR2, CD11b (a marker of granulocytes) and CD66b (a marker of neutrophils) was analyzed by immunohistochemistry on tumor samples. We demonstrated that CXCR2 stained mainly stromal cells and in particular neutrophils. CXCR2, CD11b and CD66b expression were correlated with high grade breast cancers. Moreover, TNBC displayed a higher expression of CXCR2, CD11b and CD66b than hormone receptor positive or Her2 positive tumors. High levels of CXCR2 and CD11b, but not CD66b, were associated with a higher infiltration of T lymphocytes and B lymphocytes. We also observed a correlation between CXCR2 and AP-1 activity. In univariate analyses, CXCR2, but not CD11b or CD66b, was associated with a lower risk of relapse; CXCR2 remained significant in multivariate analysis. Our data suggest that CXCR2 is a stromal marker of TNBC. However, higher levels of CXCR2 predicted a lower risk of relapse.

scholarly journals Prediction of survival after eribulin chemotherapy for breast cancer by absolute lymphocyte counts and progression types

2021 ◽  
Author(s):  
Tamami Morisaki ◽  
Shinichiro Kashiwagi ◽  
Yuka Asano ◽  
Wataru Goto ◽  
Koji Takada ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Immune Response ◽  
Cancer Progression ◽  
Locally Advanced ◽  
Tumor Biology ◽  
Metastatic Breast ◽  
The Other ◽  
Other Hand ◽  
Significant Difference ◽  
Absolute Lymphocyte Counts

Abstract Background In the RECIST diagnostic criteria, the concepts of progression by pre-existing disease (PPL) and progression by new metastases (PNM) have been proposed to distinguish between the progression types of cancer refractory to treatment. According to the tumor biology of cancer progression forms, the "PPL" form indicates invasion and the "PNM" form indicates metastasis. On the other hand, recent studies have focused on the clinical importance of inflammatory markers as indicators of the systemic tumor immune response. In particular, absolute lymphocyte counts (ALC) is an indicator of the host’s immune response. Thus, we developed a new measure that combined progression form with ALC. In this study, we clinically validated the combined assessment of progression form and ALC in eribulin chemotherapy. Methods From August 2011 to April 2019, a total of 486 patients with locally advanced or metastatic breast cancer (MBC) underwent treatment. In this study, only 88 patients who underwent chemotherapy using eribulin were included. The antitumor effect was evaluated based on the RECIST criteria, version 1.1. To measure ALC, peripheral blood samples collected before eribulin treatment were used. The cut-off value for ALC in this study was 1,500 /µL, based on previous studies. Results The PPL group (71 patients, 80.7%) had significantly longer PFS (p = 0.022, log-rank) and OS (p < 0.001, log-rank) than the PNM group (17 patients,19.3%). In the 51 patients with ALC < 1500/µl, the PPL group had a significantly better prognosis than the PNM group (PFS: p = 0.035, OS: p < 0.001, log-rank, respectively). On the other hand, in the 37 patients with ALC ≥ 1500/µl, the PPL group had a better OS compared to the PNM group (p = 0.055, log-rank), but there was no significant difference in PFS between the two groups (p = 0.541, log-rank). Furthermore, multivariate analysis that validated the effect of OS showed that high ORR and “high-ALC and PPL” were factors for a good prognosis (p < 0.001, HR = 0.321) (p = 0.036, HR = 0.290). Conclusions In breast cancer patients with eribulin chemotherapy, good systemic immune status, such as ALC ≥ 1500/µl, was associated with less progression, particularly metastasis, and better prognosis. Furthermore, the biomarker "high-ALC and PPL" was particularly useful as a prognostic marker following eribulin chemotherapy.

scholarly journals Insights from transgenic mouse models of PyMT-induced breast cancer: recapitulating human breast cancer progression in vivo

Oncogene ◽  
2020 ◽  
Author(s):  
Sherif Attalla ◽  
Tarek Taifour ◽  
Tung Bui ◽  
William Muller
Keyword(s):  
Breast Cancer ◽  
Mouse Model ◽  
Cancer Progression ◽  
Tumor Biology ◽  
T Antigen ◽  
Genetically Engineered ◽  
Breast Cancer Progression ◽  
Human Breast ◽  
Clinical Tool ◽  
Genetically Engineered Mouse Model

AbstractBreast cancer is associated with the second highest cancer-associated deaths worldwide. Therefore, understanding the key events that determine breast cancer progression, modulation of the tumor-microenvironment and metastasis, which is the main cause of cancer-associated death, are of great importance. The mammary specific polyomavirus middle T antigen overexpression mouse model (MMTV-PyMT), first published in 1992, is the most commonly used genetically engineered mouse model (GEMM) for cancer research. Mammary lesions arising in MMTV-PyMT mice follow similar molecular and histological progression as human breast tumors, making it an invaluable tool for cancer researchers and instrumental in understanding tumor biology. In this review, we will highlight key studies that demonstrate the utility of PyMT derived GEMMs in understanding the molecular basis of breast cancer progression, metastasis and highlight its use as a pre-clinical tool for therapeutic discovery.

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