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 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 Cancer-Associated Fibroblasts in Breast Cancer Treatment Response and Metastasis

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3146
Author(s):  
Patricia Fernández-Nogueira ◽  
Gemma Fuster ◽  
Álvaro Gutierrez-Uzquiza ◽  
Pere Gascón ◽  
Neus Carbó ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Hormone Receptors ◽  
Treatment Strategies ◽  
Specific Treatment ◽  
Growth Factor Receptor ◽  
Cancer Associated Fibroblasts ◽  
Luminal A ◽  
Luminal B ◽  
Number Of Patients ◽  
Current Therapies

Breast cancer (BrCa) is the leading cause of death among women worldwide, with about one million new cases diagnosed each year. In spite of the improvements in diagnosis, early detection and treatment, there is still a high incidence of mortality and failure to respond to current therapies. With the use of several well-established biomarkers, such as hormone receptors and human epidermal growth factor receptor-2 (HER2), as well as genetic analysis, BrCa patients can be categorized into multiple subgroups: Luminal A, Luminal B, HER2-enriched, and Basal-like, with specific treatment strategies. Although chemotherapy and targeted therapies have greatly improved the survival of patients with BrCa, there is still a large number of patients who relapse or who fail to respond. The role of the tumor microenvironment in BrCa progression is becoming increasingly understood. Cancer-associated fibroblasts (CAFs) are the principal population of stromal cells in breast tumors. In this review, we discuss the current understanding of CAFs’ role in altering the tumor response to therapeutic agents as well as in fostering metastasis in BrCa. In addition, we also review the available CAFs-directed molecular therapies and their potential implications for BrCa management.

Trends in breast cancer mortality according to molecular subtypes: A population-based study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 572-572
Author(s):  
Yunan Han ◽  
Shuai Xu ◽  
Graham A. Colditz ◽  
Adetunji T. Toriola
Keyword(s):  
Breast Cancer ◽  
Cancer Mortality ◽  
Triple Negative ◽  
Molecular Subtypes ◽  
Breast Cancer Mortality ◽  
Treatment Strategies ◽  
Luminal A ◽  
Her2 Positive ◽  
Mortality Trends ◽  
Luminal B

572 Background: Breast cancer is the second leading cause of cancer death in U.S. women. On the molecular level, breast cancer is a heterogeneous disease. Heterogeneous expressions of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) are etiologically and clinically meaningful, as they map to distinct risk factors and different treatment strategies. Although breast cancer mortality has been declining since 1990, little is known about mortality trends according to molecular subtypes at the population level. Methods: We examined the incidence-based mortality rates and trends among women who were diagnosed with invasive breast cancer from 2010 through 2017 using the Surveillance, Epidemiology, and End Results (SEER) database. We defined incidence-based mortality using a moving 5-year calendar period starting in 2014. We further assessed mortality according to breast cancer molecular subtypes: luminal A (ER and/or PR positive, HER2 negative), luminal B (ER and/or PR positive, HER2 positive), HER2-enriched (HER2 over-expressed or amplified, ER and PR negative) and triple-negative (ER and PR negative, HER2 negative) tumors. We calculated annual percent changes (APC) in incidence-based mortality using joinpoint regression models. Results: Overall, incidence-based mortality for breast cancer significantly decreased by 1.5% annually from 2014 through 2017 (APC, -1.5%; 95% coefficient interval [CI], -2.3% to -0.7%; p<0.001). Incidence-based mortality decreased annually by 2.0% for luminal A breast cancer (APC, -2.0%; 95% CI, -3.7% to -0.3%; p<0.001), 2.1% for luminal B breast cancer (APC, -2.1%; 95% CI, -5.4% to 1.4%; p=0.1), 1.1% for triple-negative breast cancer (TNBC) (APC, -1.1%; 95% CI, -2.1% to -0.0%; p<0.001). However, incidence-based mortality for HER2-enriched breast cancer increased 2.3% annually during the study period (APC, 2.3%; 95% CI, -2.4% to 7.2%; p=0.2). Conclusions: Between 2014 and 2017, incidence-based mortality for luminal A, luminal B, and TNBC decreased among U.S. women, with a larger decrease observed for luminal tumors. However, incidence-based mortality for HER2-enriched breast cancer increased. The favorable incidence-based mortality trends for luminal tumors and TNBC are likely due to the continuing improvement in treatments and early detection. The increasing trend of incidence-based mortality for HER2-enriched breast cancer constitutes a priority for cancer control activities and further research.

scholarly journals Stable Isotope-Resolved Metabolomic Differences between Hormone-Responsive and Triple-Negative Breast Cancer Cell Lines

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
Jason H. Winnike ◽  
Delisha A. Stewart ◽  
Wimal W. Pathmasiri ◽  
Susan L. McRitchie ◽  
Susan J. Sumner
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Triple Negative ◽  
De Novo ◽  
Tricarboxylic Acid Cycle ◽  
Treatment Strategies ◽  
Energy Utilization ◽  
Breast Cancer Cell Lines ◽  
Luminal A ◽  
Mcf 7

Purpose. To conduct an exploratory study to identify mechanisms that differentiate Luminal A (BT474 and MCF-7) and triple-negative (MDA-MB-231 and MDA-MB-468) breast cancer (BCa) cell lines to potentially provide novel therapeutic targets based on differences in energy utilization. Methods. Cells were cultured in media containing either [U-13C]-glucose or [U-13C]-glutamine for 48 hours. Conditioned media and cellular extracts were analyzed by 1H and 13C NMR spectroscopy. Results. MCF-7 cells consumed the most glucose, producing the most lactate, demonstrating the greatest Warburg effect-associated energy utilization. BT474 cells had the highest tricarboxylic acid cycle (TCA) activity. The majority of energy utilization patterns in MCF-7 cells were more similar to MDA-MB-468 cells, while the patterns for BT474 cells were more similar to MDA-MB-231 cells. Compared to the Luminal A cell lines, TNBC cell lines consumed more glutamine and less glucose. BT474 and MDA-MB-468 cells produced high amounts of 13C-glycine from media [U-13C]-glucose which was integrated into glutathione, indicating de novo synthesis. Conclusions. Stable isotopic resolved metabolomics using 13C substrates provided mechanistic information about energy utilization that was difficult to interpret using 1H data alone. Overall, cell lines that have different hormone receptor status have different energy utilization requirements, even if they are classified by the same clinical BCa subtype; and these differences offer clues about optimizing treatment strategies.

scholarly journals Chromatin Accessibility Reveals Potential Prognostic Value of the Peak Set Associated with Smoking History in Patients with Lung Adenocarcinoma

2021 ◽  
Author(s):  
Han Liang ◽  
Jianlian Deng ◽  
Tian Luo ◽  
Huijuan Luo ◽  
Xuan Wu ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Principal Component ◽  
Progression Free Survival ◽  
Chromatin Accessibility ◽  
Smoking History ◽  
Molecular Characteristics ◽  
Open Chromatin ◽  
Free Survival ◽  
Glycosphingolipid Biosynthesis ◽  
Chromatin Patterns

Abstract Considerable differences in molecular characteristics have been defined between non-smoker and smokers in patients with lung adenocarcinoma (LUAD), yet studies of open chromatin patterns associated with LUAD progression caused by smoking are still lacking. Here, we constructed a novel network based on correlations between each ATAC-seq peak from TCGA data using our previously developed algorithm. Subsequently, principal component analysis was performed on LUAD samples with retained peaks filtered by the correlation network and pathway analysis was conducted for potential pathways identification. We identified a set of peaks that discriminated smokers in LUAD patients according to levels of exposure to tobacco quantified in pack-years, and also significantly associated with progression-free survival and overall survival of these patients. We then investigated the gene set related to those peaks and found that the comprising genes are strongly associated with LUAD development, such as B3GNT3, ACTN4 and CLDN3. They are consistent with the important roles for the associated pathways in LUAD oncogenesis induced by smoking, including glycosphingolipid biosynthesis and tight junction pathways. In summary, our study may provide valuable insights on exploration of ATAC-seq peaks and on smoking-related LUAD carcinogenesis from a perspective of open chromatin changes.

scholarly journals Heterogeneity of luminal A and HER2-positive breast cancer based on DIA quantitative proteomics and bioinformatics analysis techniques

2020 ◽  
Author(s):  
Guogang Wu ◽  
Lei Zhang ◽  
Chunyan Liang ◽  
Yao Cheng ◽  
Chenguang Lv ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Treatment Strategies ◽  
Endocrine System ◽  
Luminal A ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Rho Family Gtpases ◽  
Rho Family ◽  
Cancer Tissues ◽  
Positive Breast Cancer

Abstract Background: Breast cancer has common tumor biological characteristics, but different characteristics also exist among different subtypes. Different treatment strategies have been adopted for different subtypes at present, but there are still many problems. Thus, an-depth study on the heterogeneity of different types of breast cancer will help to identify new diagnostic therapeutic targets and solve the existing problems of individualized treatment for breast cancer.Methods: In this study proteins of HER2-positive breast cancer, luminal A breast cancer, and para-cancer tissues were quantified based on data independent acquisition (DIA) proteomics technology, and the differentially expressed proteins (DEPs) were screened and analyzed by IPA software and the database among the luminal A (LA ) versus para-cancer tissues (PT) and HER2 versus LA groups.Results: There were 264 up- and 123 down-regulated proteins in the LA versus PT groups. PD-1 and PD-L1 cancer immunotherapy pathways were significantly inhibited, and XBP1 was predicted to be the strongest activator. MTOR was predicted to be the strongest inhibitor. The DEPs were significantly associated with “Cancer” and “Organismal Injury and Abnormalities.” There were 134 up- and 286 down-regulated proteins in the HER2 versus LA groups. Signaling by rho family GTPases was significantly inhibited. XBP1 was predicted to be the strongest activator. TGFB1 was predicted to be the strongest inhibitor. The DEPs were significantly associated with “Cancer,” “Endocrine System Disorders,” and “Organismal Injury and Abnormalities.”Conclusion: Luminal A breast cancer may be insensitive to PD-1 and PD-L1 inhibitors. Signaling by rho family GTPases and RhoGDI signaling play a unique role in the proliferation and metastasis of luminal A and HER2-positive breast cancer, respectively. XBP1 is a promising new target for the treatment of breast cancer, and TGFB1 may play different biological roles in HER2-positive and luminal A breast cancer.

scholarly journals Inferences from dysregulated long non-coding RNA-mediated competing endogenous RNAs in various chemotherapy drugs and evaluation of drug response in breast cancer

2020 ◽  
Author(s):  
Ziwen Zhang ◽  
Dongbo Li ◽  
Han Zhang ◽  
Qi Qin ◽  
Qingyuan Zhang
Keyword(s):  
Breast Cancer ◽  
Drug Response ◽  
Treatment Strategies ◽  
Molecular Characteristics ◽  
Cancer Hallmarks ◽  
Chemotherapy Drugs ◽  
Non Coding Rna ◽  
Competing Endogenous Rnas ◽  
Novel Treatment Strategies ◽  
Long Non Coding Rna

Abstract Backgroud: Differences in individual drug response, especially drug resistance, present an obstacle to the treatment of breast cancer (BRCA). Thus, the ability to predict drug response would contribute to developing novel treatment strategies. Accumulating evidence have suggested that tumor molecular profiles and drug response data provide opportunities and challenges for the discovery of new molecular characteristics and mechanisms of drug response in BRCA. Methods: In the present study, an integrated pipeline was developed to explore drug response-related long non-coding RNA (lncRNA)-mediated competing endogenous RNAs (ceRNAs) motifs in BRCA. Results: Drug response-specific ceRNAs indicated that lncRNAs play an essential role in various drug treatments for BRCA. Several key drug-resistant and -sensitive dysregulated ceRNAs were identified in Adriamycin, Cytoxan, and Tamoxifen. The interactions in these ceRNAs showed strong correlations in BRCA. Most drug response-related dysregulated ceRNAs were only present in one kind of drug. A number of drug response-related ceRNAs presented diverse dysregulation patterns. We also extracted some key drug response-related lncRNAs, such as HCP5 and FAM182A. These lncRNAs were associated with certain cancer hallmarks and survival in BRCA. Conclusions: Ultimately, understanding the underlying lncRNA-mediated ceRNAs in drug responses will facilitate improved individual reactions to chemotherapy and overall outcomes of BRCA treatment.

scholarly journals miRNA Expression Profiles in Luminal A Breast Cancer—Implications in Biology, Prognosis, and Prediction of Response to Hormonal Treatment

2020 ◽  
Vol 21 (20) ◽  
pp. 7691
Author(s):  
Erik Kudela ◽  
Marek Samec ◽  
Lenka Koklesova ◽  
Alena Liskova ◽  
Peter Kubatka ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Mirna Expression ◽  
Early Stage ◽  
Expression Profiles ◽  
Classification Systems ◽  
Molecular Characteristics ◽  
Breast Cancer Patients ◽  
Luminal A ◽  
Altered Expression ◽  
Cancer Subtypes

Breast cancer, which is the most common malignancy in women, does not form a uniform nosological unit but represents a group of malignant diseases with specific clinical, histopathological, and molecular characteristics. The increasing knowledge of the complex pathophysiological web of processes connected with breast cancercarcinogenesis allows the development of predictive and prognostic gene expressionand molecular classification systems with improved risk assessment, which could be used for individualized treatment. In our review article, we present the up-to-date knowledge about the role of miRNAs and their prognostic and predictive value in luminal A breast cancer. Indeed, an altered expression profile of miRNAs can distinguish not only between cancer and healthy samples, but they can classify specific molecular subtypes of breast cancer including HER2, Luminal A, Luminal B, and TNBC. Early identification and classification of breast cancer subtypes using miRNA expression profilescharacterize a promising approach in the field of personalized medicine. A detection of sensitive and specific biomarkers to distinguish between healthy and early breast cancer patients can be achieved by an evaluation of the different expression of several miRNAs. Consequently, miRNAs represent a potential as good diagnostic, prognostic, predictive, and therapeutic biomarkers for patients with luminal A in the early stage of BC.

scholarly journals Lobular Breast Cancer: Histomorphology and Different Concepts of a Special Spectrum of Tumors

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3695
Author(s):  
Matthias Christgen ◽  
Gábor Cserni ◽  
Giuseppe Floris ◽  
Caterina Marchio ◽  
Lounes Djerroudi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative ◽  
Tumor Biology ◽  
Treatment Strategies ◽  
Special Treatment ◽  
Molecular Characteristics ◽  
Lobular Breast Cancer ◽  
Her2 Positive ◽  
Comprehensive Overview ◽  
Invasive Lobular Breast Cancer

Invasive lobular breast cancer (ILC) is the most common special histological type of breast cancer (BC). This review recapitulates developments in the histomorphologic assessment of ILC from its beginnings with the seminal work of Foote and Stewart, which was published in 1941, until today. We discuss different concepts of ILC and their implications. These concepts include (i) BC arising from mammary lobules, (ii) BC growing in dissociated cells and single files, and (iii) BC defined as a morpho-molecular spectrum of tumors with distinct histological and molecular characteristics related to impaired cell adhesion. This review also provides a comprehensive overview of ILC variants, their histomorphology, and differential diagnosis. Furthermore, this review highlights recent advances which have contributed to a better understanding of the histomorphology of ILC, such as the role of the basal lamina component laminin, the molecular specificities of triple-negative ILC, and E-cadherin to P-cadherin expression switching as the molecular determinant of tubular elements in CDH1-deficient ILC. Last but not least, we provide a detailed account of the tumor microenvironment in ILC, including tumor infiltrating lymphocyte (TIL) levels, which are comparatively low in ILC compared to other BCs, but correlate with clinical outcome. The distinct histomorphology of ILC clearly reflects a special tumor biology. In the clinic, special treatment strategies have been established for triple-negative, HER2-positive, and ER-positive BC. Treatment specialization for patients diagnosed with ILC is just in its beginnings. Accordingly, ILC deserves greater attention as a special tumor entity in BC diagnostics, patient care, and cancer research.

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