Mast cells in luminal vs non-luminal breast cancers

Background: Tumor growth and development is determined by the mutual interaction between the cancer cells themselves and the microenvironment. It contains various elements, including immune cells. Of all, mast cells have one of the most controversial roles. The aim of the present study was to evaluate the expression of mast cell tryptase in the luminal and non-luminal subtypes of breast cancer and establish a possible link between infiltration with MCs and expression of hormone receptors. Material and methods: The experimental study included 80 cases of breast carcinomas that were analyzed immunohistochemically in order to establish the molecular profile and the expression of tryptase, a specific marker of mast cells. The data were processed using the SPSS program. Pearson’s coefficient (r) and the other values were considered statistically significant in case of p≤0.05. Results: Both intratumoral mast cells (MCit) and peritumoral mast cells (MCpt) correlated with the expression of hormone receptors for estrogen (ER) and progesterone (PR). Thus, the following relations were established: MCit and ER (r=0.343, p=0.002), MCpt and ER (r=0.394, p=0.000295) and MCpt and PR (r=0.386, p=0.000409). Statistically significant correlations between HER2 expression and mast cells content have not been established. Conclusions: Mast cells invasion, peri- and intratumoral, is strongly influenced by the expression of hormone receptors. The luminal subtypes of breast cancer are characterized by a higher density of mast cells.

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CBP/p300: Critical Co-Activators for Nuclear Steroid Hormone Receptors and Emerging Therapeutic Targets in Prostate and Breast Cancers

Cancers ◽

10.3390/cancers13122872 ◽

2021 ◽

Vol 13 (12) ◽

pp. 2872

Author(s):

Aaron R. Waddell ◽

Haojie Huang ◽

Daiqing Liao

Keyword(s):

Breast Cancer ◽

Prostate Cancer ◽

Tumor Growth ◽

Signaling Pathways ◽

Cell Cycle Progression ◽

Hormone Receptors ◽

Steroid Hormone Receptors ◽

Breast Cancers ◽

Creb Binding Protein ◽

Breast And Prostate Cancer

The CREB-binding protein (CBP) and p300 are two paralogous lysine acetyltransferases (KATs) that were discovered in the 1980s–1990s. Since their discovery, CBP/p300 have emerged as important regulatory proteins due to their ability to acetylate histone and non-histone proteins to modulate transcription. Work in the last 20 years has firmly established CBP/p300 as critical regulators for nuclear hormone signaling pathways, which drive tumor growth in several cancer types. Indeed, CBP/p300 are critical co-activators for the androgen receptor (AR) and estrogen receptor (ER) signaling in prostate and breast cancer, respectively. The AR and ER are stimulated by sex hormones and function as transcription factors to regulate genes involved in cell cycle progression, metabolism, and other cellular functions that contribute to oncogenesis. Recent structural studies of the AR/p300 and ER/p300 complexes have provided critical insights into the mechanism by which p300 interacts with and activates AR- and ER-mediated transcription. Breast and prostate cancer rank the first and forth respectively in cancer diagnoses worldwide and effective treatments are urgently needed. Recent efforts have identified specific and potent CBP/p300 inhibitors that target the acetyltransferase activity and the acetytllysine-binding bromodomain (BD) of CBP/p300. These compounds inhibit AR signaling and tumor growth in prostate cancer. CBP/p300 inhibitors may also be applicable for treating breast and other hormone-dependent cancers. Here we provide an in-depth account of the critical roles of CBP/p300 in regulating the AR and ER signaling pathways and discuss the potential of CBP/p300 inhibitors for treating prostate and breast cancer.

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The Roles of DNA Demethylases in Triple-Negative Breast Cancer

Pharmaceuticals ◽

10.3390/ph14070628 ◽

2021 ◽

Vol 14 (7) ◽

pp. 628

Author(s):

Shoghag Panjarian ◽

Jean-Pierre J. Issa

Keyword(s):

Breast Cancer ◽

Dna Methylation ◽

Tumor Suppressor Genes ◽

Hormone Receptors ◽

Triple Negative ◽

Breast Cancers ◽

Therapeutic Implications ◽

High Propensity ◽

Dna Methylation Profile

Triple-negative breast cancers (TNBCs) are very heterogenous, molecularly diverse, and are characterized by a high propensity to relapse or metastasize. Clinically, TNBC remains a diagnosis of exclusion by the lack of hormone receptors (Estrogen Receptor (ER) and Progesterone Receptor (PR)) as well as the absence of overexpression and/or amplification of HER2. DNA methylation plays an important role in breast cancer carcinogenesis and TNBCs have a distinct DNA methylation profile characterized by marked hypomethylation and lower gains of methylations compared to all other subtypes. DNA methylation is regulated by the balance of DNA methylases (DNMTs) and DNA demethylases (TETs). Here, we review the roles of TETs as context-dependent tumor-suppressor genes and/or oncogenes in solid tumors, and we discuss the current understandings of the oncogenic role of TET1 and its therapeutic implications in TNBCs.

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Transcriptome profiles of stem-like cells from primary breast cancers allow identification of ITGA7 as a predictive marker of chemotherapy response

British Journal of Cancer ◽

10.1038/s41416-021-01484-w ◽

2021 ◽

Author(s):

Noha Gwili ◽

Stacey J. Jones ◽

Waleed Al Amri ◽

Ian M. Carr ◽

Sarah Harris ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Predictive Marker ◽

Therapy Resistance ◽

Differentially Expressed ◽

Molecular Profile ◽

Chemotherapy Response ◽

Breast Cancers

Abstract Background Breast cancer stem cells (BCSCs) are drivers of therapy-resistance, therefore are responsible for poor survival. Molecular signatures of BCSCs from primary cancers remain undefined. Here, we identify the consistent transcriptome of primary BCSCs shared across breast cancer subtypes, and we examine the clinical relevance of ITGA7, one of the genes differentially expressed in BCSCs. Methods Primary BCSCs were assessed using immunohistochemistry and fluorescently labelled using Aldefluor (n = 17). Transcriptomes of fluorescently sorted BCSCs and matched non-stem cancer cells were determined using RNA-seq (n = 6). ITGA7 expression was examined in breast cancers using immunohistochemistry (n = 305), and its functional role was tested using siRNA in breast cancer cells. Results Proportions of BCSCs varied from 0 to 9.4%. 38 genes were significantly differentially expressed in BCSCs; genes were enriched for functions in vessel morphogenesis, motility, and metabolism. ITGA7 was found to be significantly downregulated in BCSCs, and low expression significantly correlated with reduced survival in patients treated with chemotherapy, and with chemoresistance in breast cancer cells in vitro. Conclusions This study is the first to define the molecular profile of BCSCs from a range of primary breast cancers. ITGA7 acts as a predictive marker for chemotherapy response, in accordance with its downregulation in BCSCs.

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Predominance of RAD21 and ERBB2 amplification and progesterone receptor positivity in tumors of the right breast support breast cancer lateralization.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e12557 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e12557-e12557

Author(s):

Zachary Spigelman ◽

Jo-Ellen Murphy

Keyword(s):

Breast Cancer ◽

Progesterone Receptor ◽

Cancer Patients ◽

Breast Tumors ◽

Left Breast ◽

Breast Cancers ◽

Her2 Expression ◽

Breast Cancer Patients ◽

The Right ◽

Chi Square Analysis

e12557 Background: Biologic lateralization broadly impacts breast cancer. Malignancies originating in the left breast compared to the right breast tend to be more frequent, larger and of poorer prognosis. Left breast tumors respond differently to HER2-neu signaling and have lateralized Ki67 expression. In a prior study a right-left asymmetry in the neutrophil/lymphocyte ratio (NLR) of breast cancers was identified (ASCO 2018, e13094). As a follow-up, retrospective analysis of results from comprehensive genomic profiling (CGP) of right and left side breast cancer specimens was performed to determine a potential genomic etiology for the observed NLR lateralization. Methods: Tumors from 43 consecutive breast cancer patients underwent analysis for all classes of genomic alterations by hybrid capture-based CGP (Foundation Medicine). The CGP results from the 25 left- and 18 right-sided breast cancer samples were analyzed along with the histologic grade and status of estrogen receptor (ER), progesterone receptor (PR), and HER2 expression. Results: In this cohort of advanced breast cancer patients (stage 3-4), no statistically significant differences in lateralization were identified based on patient age, tumor stage, or frequency of ER or Her2 expression (Table). A predominance of PR positivity (p=0.14 chi square analysis) and amplifications in the ERBB2 (p=0.37) and RAD21 (p=0.08) genes were detected in right side tumors. Conclusions: Together with the prior study, trends in asymmetry based on genomic, pathologic, and immunohistologic differences have been detected in breast cancers, including an increased incidence of ERBB2 and RAD21 amplification in right-side breast tumors in this cohort. The predominance of lower PR positivity in the left breast tumors may be due to preferential hypermethylation, consistent with reports that it mediates biologic lateralization changes, downregulates PR expression, and alters amplification rates. Epigenetic methylation, may contribute to asymmetric breast cancer biology and have implications for therapeutic strategy. Further study is warranted.[Table: see text]

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Breast cancer ER, PR, and HER2 expression variance by germline cancer predisposition genes.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.10526 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 10526-10526

Author(s):

Grace Wei ◽

Marilin Rosa ◽

Maxine Chang ◽

Brian J. Czerniecki ◽

Xia Wang

Keyword(s):

Breast Cancer ◽

Cancer Diagnosis ◽

Breast Cancer Diagnosis ◽

Cancer Predisposition ◽

Tumor Evolution ◽

Breast Cancers ◽

Her2 Expression ◽

Expression Levels ◽

Genetic Test Results ◽

Predisposition Genes

10526 Background: The association between breast cancer characteristics and survival with estrogen receptor (ER) and progesterone receptor (PR) expression has been primarily studied via binomial categories, ER-positive and ER-negative. In order to better characterize germline genetic influences on these markers, we investigated their IHC expression semi-quantitatively in cancer predisposition germline pathogenic variant (PV) carriers of the following genes: BRCA1, BRCA2, PALB2, TP53, PTEN, CDH1, ATM, CHEK2, and Lynch syndrome genes. The HER2 expression was also analyzed. Methods: We conducted a retrospective chart review of patients with germline panel genetic testing for cancer predisposition genes at Moffitt Cancer Center’s GeneHome clinic. Inclusion criteria included 1) women ≥18 years old, 2) breast cancer diagnosis, 3) cancer predisposition germline panel genetic test results, 4) available ER and PR expression levels, and 5) available HER expression and/or amplification status. ER, PR, and HER2 status were compared between PV carriers and non-PV carriers via Mann-Whitney U at p>0.05. Results: A total of 847 cases were reviewed for the study. Among 658 patients with a breast cancer diagnosis and complete ER PR data, 365 cases (55.5%) were non-PV carriers and 293 cases (44.5%) carried a PV in at least one of the genes listed above. Among 635 cases with available HER2 expression/amplification status, 355 (55.9%) cases were non-PV carriers and 288 (45.4%) cases were PV-carriers. When compared with non-PV carrier controls, BRCA1 PV carriers’ breast tumors had significantly lower ER and/or PR expression. Further, BRCA2 and TP53 PV tumors also displayed moderately lower ER expression. Contrarily, CHEK2 tumors displayed higher ER and PR expression compared to controls. Further, BRCA1 and BRCA2 PV carriers were more likely to have HER2- breast cancers. Conclusions: Differences in ER, PR, HER2 expression levels were observed in germline PV carrier breast cancers, signaling differential impacts by germline PVs on the tumor evolution process. It is likely that tumor differences in PV carriers influence responses to therapies, including hormone therapy, anti-HER2 therapy, and subsequent survival.[Table: see text]

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CILP Inhibits Brain Metastasis by Meditating Mast Cells via the MAPK Signaling Pathway in Breast Cancer

10.21203/rs.3.rs-328026/v1 ◽

2021 ◽

Author(s):

Xiaolin Sun ◽

Xingguo Zhou ◽

Alei Feng ◽

Gongwen Xu ◽

Qiang Wang ◽

...

Keyword(s):

Breast Cancer ◽

Mast Cells ◽

Correlation Analysis ◽

Brain Metastases ◽

Signaling Pathway ◽

Immune Cells ◽

Cell Activity ◽

Mapk Signaling ◽

High Morbidity ◽

Spearman’S Correlation

Abstract Background: Approximately 15–30% of patients with breast cancer (BRCA) eventually develop brain metastases (BMs) with high morbidity and mortality. Herein, we aimed to identify genes specific to breast cancer brain metastases (BCBM) from an immune infiltration perspective.Methods: GSE100534 and GSE125989 were obtained from the NCBI Gene Expression Omnibus (GEO), then performed normalization using Rstudio and perl 5. We constructed a Weighted Gene Co-Expression Network Analysis (WGCNA) and obtained differentially expressed genes (DEGs) in BMs sample compared with primary BRCA tissue. Then we performed GO and KEGG pathway analysis. The LinkedOmics and UALCAN analysis showed the expression of gene in BRCA. The Kaplan-Meier plotter database was used to evaluate the prognosis. The composition of significant tumor-infiltrating immune cells was assessed using the CIBERSORT algorithm. Spearman’s correlation analysis revealed the correlation between CILP gene and immune cells in TCGA cohort and Timer database. Using GSEA analysis, we conducted to identify the potential pathways in BCBM.Results: The cartilage intermediate layer protein (CILP) was a late event in BRCA (stage III to IV) with poor prognosis (P< 0.05). LinkedOmics showed that the mRNA expression of CILP was down-regulated in advanced cancer (P< 0.05). Besides, UALCAN analysis showed that CILP expression was downregulated in HER2-positive and triple-negative breast cancer which were more prone to BMs (P< 0.05). CILP was the hub gene which was significantly associated with BCBM identified by WGCNA (R2=−0.6, P=3e-06). We found that the resting infiltration of mast cells in the BCBM group was significantly lower than that in the primary BRCA group (P= 0.01). In addition, Spearman’s correlation analysis revealed that the expression of CILP positively correlated with that of mast cells (P< 0.05). Finally, the FCERI-mediated MAPK activation (NES=2.1847, P=0, FDR=0.0031), which could regulate mast cell activity, were enriched in BCBM.Conclusions: CILP can influence the progression of BRCA favored for BMs through meditating mast cells via the MAPK signaling pathway.

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O-linked mucin-type glycosylation in breast cancer

Biochemical Society Transactions ◽

10.1042/bst20170483 ◽

2018 ◽

Vol 46 (4) ◽

pp. 779-788 ◽

Cited By ~ 20

Author(s):

Joy M. Burchell ◽

Richard Beatson ◽

Rosalind Graham ◽

Joyce Taylor-Papadimitriou ◽

Virginia Tajadura-Ortega

Keyword(s):

Breast Cancer ◽

Endoplasmic Reticulum ◽

Immune Cells ◽

Therapeutic Intervention ◽

Tumour Growth ◽

Breast Cancers ◽

Altered Expression ◽

Surface Receptors

Changes in mucin-type O-linked glycosylation are seen in over 90% of breast cancers where increased sialylation is often observed and a change from branched glycans to linear glycans is often seen. There are many mechanisms involved including increased/altered expression of glycosyltransferases and relocalisation to the endoplasmic reticulum of the enzymes responsible for the addition of the first sugar, N-acetyl-d-galactosamine. It is now becoming clear that these changes can contribute to tumour growth and progression by modulating the micro-environment through glycan-sensing lectins expressed on immune cells, by modulating interactions with tumour surface receptors and by binding to selectins. The understanding of how changes in mucin-type O-linked glycosylation influence tumour growth and progression reveals new potential targets for therapeutic intervention in the treatment of breast cancer.

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Analysis of Low Estrogen Receptor (ER+) Breast Carcinomas in a Large Community Breast Cancer Center in Northern California

American Journal of Clinical Pathology ◽

10.1093/ajcp/aqab191.051 ◽

2021 ◽

Vol 156 (Supplement_1) ◽

pp. S26-S27

Author(s):

G Bulusu ◽

K Duncan ◽

A Wheeler

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Histological Grade ◽

Statistical Significance ◽

Cancer Center ◽

Pathology Report ◽

Breast Cancers ◽

Breast Carcinomas ◽

Ki 67 ◽

Er Positive

Abstract Introduction/Objective Estrogen Receptor (ER) expression in breast cancers is a crucial factor for endocrine therapy in patients with tumors expressing ER in ≥1% of tumor cells. The 2019 guidelines published by ASCO/CAP states that breast cancers that have a 1% to 10% of cells staining Estrogen Receptor (ER) positive should be reported as ER Low Positive cases. This study aims to address this subset of low-positive ER tumors and compare the clinical features to other known breast cancer subtypes. Methods/Case Report We conducted a retrospective review of a prospectively maintained breast cancer registry from 2013 to 2021 at Mills-Peninsula Medical Center, a Sutter Health Affiliate. The study reviewed patient charts with respect to the pathology report, operative report, chemotherapy regimen, and clinical outcomes. Statistical analyses were conducted using R Project for Statistical Coding, with The Student’s T-test used to compare continuous variables. Two-sided P values less than 0.05 indicate statistical significance. Results (if a Case Study enter NA) Our study identified 1316 cases of invasive breast carcinomas, of which 29 (2.16%) demonstrated ER Low-Positive expression. We aimed to evaluate the clinical and pathological features, such as histological grade, ER, PR, HER-2, Ki-67%, and patient age for these tumors. We found that ER Low-Positive tumors demonstrated higher mean histological grade morphology (2.5 out of 3, p<0.001) that was similar to that of Triple Negative Breast Cancers (TNBC) (3 of 3, p<0.001) than to High ER-Positive (1.6 of 3, p<0.001) cancers. Further observations, through examining proliferation rates by utilizing the Ki-67 index, indicate comparative trends between the ER Low-Positive cohort and the TNBC cohort. Conclusion The results suggest that the ER Low-Positive carcinomas, despite reported as ER-positive cases, present with similar clinicopathological features to those of ER-negative tumors. Through this study and future research, we would like to emphasize a stricter set of guidelines that can be adopted to reduce variability for reporting biomarkers. This standardization will allow oncologists to provide more appropriate treatment options and improve the quality of patient care.

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Practical Approach to Triple-Negative Breast Cancer

Journal of Oncology Practice ◽

10.1200/jop.2017.022632 ◽

2017 ◽

Vol 13 (5) ◽

pp. 293-300 ◽

Cited By ~ 24

Author(s):

Vijayakrishna K. Gadi ◽

Nancy E. Davidson

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Hormone Receptors ◽

Triple Negative ◽

Early Stage ◽

Management Strategies ◽

Growth Factor Receptor ◽

Breast Cancers ◽

Epidermal Growth ◽

Proven Method

Triple negative is a term applied to breast cancers that do not meaningfully express the estrogen or progesterone hormone receptors or overexpress the human epidermal growth factor receptor 2 tyrosine kinase. At present, the only proven method for systemic management of triple-negative breast cancer for both early-stage and metastatic settings is cytotoxic chemotherapy. Here, we provide a comprehensive review of management strategies that are best supported by available data. We also review recent advances most likely to affect treatment of triple-negative breast cancer in the coming years with particular emphasis on targeted agents, biologics, and immunotherapy.

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Molecular Profile and Clinical Variables in Brca1-Positive Breast Cancers. A Population-Based Study

Tumori Journal ◽

10.1177/030089160509100611 ◽

2005 ◽

Vol 91 (6) ◽

pp. 505-512 ◽

Cited By ~ 12

Author(s):

Antonino Musolino ◽

Maria Michiara ◽

Maria A. Bella ◽

Nadia Naldi ◽

Paola Zanelli ◽

...

Keyword(s):

Breast Cancer ◽

Direct Sequencing ◽

Population Based ◽

Molecular Profile ◽

Breast Cancers ◽

Population Based Study ◽

Free Survival ◽

Molecular Features ◽

Inherited Susceptibility ◽

Brca1 Mutations

Purpose To evaluate the clinical features of breast cancer patients with genetic susceptibility to this disease and to investigate the contribution of BRCA1 germline mutations to the phenotype of these tumors. Patients and Methods We reviewed the clinical and pathological records of 102 women with suspected inherited susceptibility to breast cancer consecutively seen at the Genetic Oncology Service of Parma, Italy. Sixty-two patients with a high probability of harboring a germline, cancer-predisposing mutation were tested for BRCA1 mutations. Exon 11 was screened using the protein truncation test and detected mutations were confirmed by direct sequencing (DS). All other exons were analyzed by DS. Results Among the 62 patients with a completed mutation analysis, 48 (77.4%) had wild-type BRCA1, six (9.6%) had variants of unclear significance, eight (13%) had deleterious mutations. BRCA1-associated breast cancers (BABC) were significantly less likely to be diagnosed at stage I than breast cancers in women without mutations (12.5% vs 51%; P = 0.045), more likely to have a high proliferation rate (100% vs 24%, P<0.001), and more likely to be histological grade 3 (100% vs 14%, P<0.001), estrogen and progesterone receptor negative (87.5% vs 13%, P<0.001; 75% vs 23%, P = 0.004), and p53 positive (87.5% vs 30%, P = 0.023). All tumors with BRCA1 mutations were HER-2/neu negative compared with 57% of the non-BRCA1 tumors ( P = 0.04). There were no significant differences between BABC and non-BABC in 20-year relapse-free survival, 20-year event-free survival, and 20-year overall survival. Conclusion In this population-based study, BABC seems to present with adverse molecular features when compared with non-BABC, although the prognosis appears to be similar.

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