scholarly journals Circulating Low Density Neutrophils of Breast Cancer Patients are Associated with their Worse Prognosis due to the Impairment of T cell Responses

2021 ◽  
Author(s):  
Diana P. Saraiva ◽  
Bruna F. Correia ◽  
Rute Salvador ◽  
Nídia de Sousa ◽  
António Jacinto ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ex Vivo ◽  
Tumor Development ◽  
Poor Response ◽  
Response To Treatment ◽  
Low Density ◽  
Breast Cancer Patients ◽  
Activation Markers ◽  
Healthy Donors ◽  
Worse Prognosis

AbstractNeutrophils are prominent immune components of solid tumors, which can protect against the onset of cancer (N1) or have pro-tumor activity (N2). Circulating neutrophils, divided into high density neutrophils (HDN) and low density neutrophils (LDN), functionally mirror those N1 and N2 cells, respectively. LDN, a rare subset in non-pathological conditions, have been extensively studied in cancer, due to their frequency in this disease and their pro-tumor phenotype. However, this has been mainly demonstrated in animal models and proper validation in humans is an urgent need. Here, we further enlighten the clinical impact of LDN in a cohort of breast cancer (BC) patients. We observed that LDN were practically absent in healthy donors’ blood, while were significantly increased in the blood of BC patients, particularly with metastatic disease. Relevant for a clinical translation, within the population of non-metastatic patients, LDN were more prevalent in patients with poor response to neoadjuvant chemotherapy than in responders. The association of a higher incidence of circulating LDN and the worse prognosis of BC patients could be explained by the pro-tumor/immunosuppressive characteristics exhibited by these cells. Namely, there are more LDN expressing the immunosuppressive marker PD-L1, than HDN. Additionally, LDN also showed increased expression of activation markers; a robust formation of neutrophil extracellular traps; an augmented phagocytic activity; and a higher capacity to release reactive oxygen species, which may contribute for tumor development and metastization. Moreover, the percentage of LDN in BC patients’ blood was negatively correlated with activated cytotoxic T lymphocytes and positively correlated with the immunosuppressive CCR4+ regulatory T cells, corroborating their impairment on the anti-tumor immune responses, which was further demonstrated ex vivo. Hence, this study reveals the potential of LDN as a clinical meaningful biomarker of BC response to treatment and opens new avenues for developing targeted immunotherapies.

New Scm (Structuredness of the Cytoplasmatic Matrix)-Based Approach in Breast Cancer Detection

1996 ◽  
Vol 82 (6) ◽  
pp. 550-553 ◽  
Author(s):  
Sarah Birindelli ◽  
Maria Ines Colnaghi ◽  
Silvana Pilotti
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Tumor Development ◽  
Cellular Membrane ◽  
Suppressor Gene ◽  
Breast Cancer Patients ◽  
Therapeutic Approaches ◽  
Healthy Donors ◽  
Significant Difference ◽  
Healthy Female

Aims and Background We evaluate the possibility to use a combination of techniques such as lymphocyte stimulation and the Cell Scan instrument for early detection of breast cancer. This method can detect differences in lymphocytes activation in the presence or absence of cancer. Methods The Cell Scan is a static cytometer system able to examine cellular membrane polarization. We screened 88 women with benign breast lesions, 207 women with mammary carcinoma and 325 healthy blood donors. After lymphocytes separation, each blood sample was incubated with encephalitogenic factor (EF), phytohaemagglutinin (PHA) and Breast Antigen (BrAg) then SCM test was performed. Results Positivity was 50% among breast cancer patients, 34% among women affected by benign disease and 27% and 22% respectively among healthy female and male controls with an increase of the specific predictivity of the test during the period of ovulation. A significant difference ( P <0.0001) was observed between healthy donors and breast cancer patients. Conclusions This results suggest that the Cell Scan test could be useful to investigate patient's immunogenicity to molecules known to be involved in tumor development and progression, such as oncogene or suppressor gene products, which could be appropriate targets for immune-derived therapeutic approaches.

scholarly journals Mapping of Genomic Vulnerabilities in the Post-Translational Ubiquitination, SUMOylation and Neddylation Machinery in Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 833
Author(s):  
Jesús Fuentes-Antrás ◽  
Ana Lucía Alcaraz-Sanabria ◽  
Esther Cabañas Morafraile ◽  
María del Mar Noblejas-López ◽  
Eva María Galán-Moya ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Development ◽  
Gene Mutations ◽  
Complete Response ◽  
Breast Cancer Patients ◽  
Clinical Value ◽  
Luminal A ◽  
Genomic Alterations ◽  
Cancer Hallmarks ◽  
Worse Prognosis

The dysregulation of post-translational modifications (PTM) transversally impacts cancer hallmarks and constitutes an appealing vulnerability for drug development. In breast cancer there is growing preclinical evidence of the role of ubiquitin and ubiquitin-like SUMO and Nedd8 peptide conjugation to the proteome in tumorigenesis and drug resistance, particularly through their interplay with estrogen receptor signaling and DNA repair. Herein we explored genomic alterations in these processes using RNA-seq and mutation data from TCGA and METABRIC datasets, and analyzed them using a bioinformatic pipeline in search of those with prognostic and predictive capability which could qualify as subjects of drug research. Amplification of UBE2T, UBE2C, and BIRC5 conferred a worse prognosis in luminal A/B and basal-like tumors, luminal A/B tumors, and luminal A tumors, respectively. Higher UBE2T expression levels were predictive of a lower rate of pathological complete response in triple negative breast cancer patients following neoadjuvant chemotherapy, whereas UBE2C and BIRC5 expression was higher in luminal A patients with tumor relapse within 5 years of endocrine therapy or chemotherapy. The transcriptomic signatures of USP9X and USP7 gene mutations also conferred worse prognosis in luminal A, HER2-enriched, and basal-like tumors, and in luminal A tumors, respectively. In conclusion, we identified and characterized the clinical value of a group of genomic alterations in ubiquitination, SUMOylation, and neddylation enzymes, with potential for drug development in breast cancer.

scholarly journals Early, On-Treatment Levels and Dynamic Changes of Genomic Instability in Circulating Tumor DNA Predict Response to Treatment and Outcome in Metastatic Breast Cancer Patients

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1331
Author(s):  
Adriana Aguilar-Mahecha ◽  
Josiane Lafleur ◽  
Susie Brousse ◽  
Olga Savichtcheva ◽  
Kimberly A. Holden ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Genomic Instability ◽  
Metastatic Cancer ◽  
Metastatic Breast ◽  
Circulating Tumor Dna ◽  
Response To Treatment ◽  
Breast Cancer Patients ◽  
T1 And T2 ◽  
Tumor Dna

Background: Circulating tumor DNA (ctDNA) offers high sensitivity and specificity in metastatic cancer. However, many ctDNA assays rely on specific mutations in recurrent genes or require the sequencing of tumor tissue, difficult to do in a metastatic disease. The purpose of this study was to define the predictive and prognostic values of the whole-genome sequencing (WGS) of ctDNA in metastatic breast cancer (MBC). Methods: Plasma from 25 patients with MBC were taken at the baseline, prior to treatment (T0), one week (T1) and two weeks (T2) after treatment initiation and subjected to low-pass WGS. DNA copy number changes were used to calculate a Genomic Instability Number (GIN). A minimum predefined GIN value of 170 indicated detectable ctDNA. GIN values were correlated with the treatment response at three and six months by Response Evaluation Criteria in Solid Tumours assessed by imaging (RECIST) criteria and with overall survival (OS). Results: GIN values were detectable (>170) in 64% of patients at the baseline and were significantly prognostic (41 vs. 18 months OS for nondetectable vs. detectable GIN). Detectable GIN values at T1 and T2 were significantly associated with poor OS. Declines in GIN at T1 and T2 of > 50% compared to the baseline were associated with three-month response and, in the case of T1, with OS. On the other hand, a rise in GIN at T2 was associated with a poor response at three months. Conclusions: Very early measurements using WGS of cell-free DNA (cfDNA) from the plasma of MBC patients provided a tumor biopsy-free approach to ctDNA measurement that was both predictive of the early tumor response at three months and prognostic.

scholarly journals Abnormal Long Non-Coding RNAs Expression Patterns Have the Potential Ability for Predicting Survival and Treatment Response in Breast Cancer

Genes ◽  
2021 ◽  
Vol 12 (7) ◽  
pp. 996
Author(s):  
Ana Carolina Pavanelli ◽  
Flavia Rotea Mangone ◽  
Luciana R. C. Barros ◽  
Juliana Machado-Rugolo ◽  
Vera L. Capelozzi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Predictive Value ◽  
Expression Patterns ◽  
Survival Rates ◽  
In Silico Analysis ◽  
Cancer Prognosis ◽  
Response To Treatment ◽  
Breast Cancer Patients ◽  
Non Coding Rnas

Abnormal long non-coding RNAs (lncRNAs) expression has been documented to have oncogene or tumor suppressor functions in the development and progression of cancer, emerging as promising independent biomarkers for molecular cancer stratification and patients’ prognosis. Examining the relationship between lncRNAs and the survival rates in malignancies creates new scenarios for precision medicine and targeted therapy. Breast cancer (BRCA) is a heterogeneous malignancy. Despite advances in its molecular classification, there are still gaps to explain in its multifaceted presentations and a substantial lack of biomarkers that can better predict patients’ prognosis in response to different therapeutic strategies. Here, we performed a re-analysis of gene expression data generated using cDNA microarrays in a previous study of our group, aiming to identify differentially expressed lncRNAs (DELncRNAs) with a potential predictive value for response to treatment with taxanes in breast cancer patients. Results revealed 157 DELncRNAs (90 up- and 67 down-regulated). We validated these new biomarkers as having prognostic and predictive value for breast cancer using in silico analysis in public databases. Data from TCGA showed that compared to normal tissue, MIAT was up-regulated, while KCNQ1OT1, LOC100270804, and FLJ10038 were down-regulated in breast tumor tissues. KCNQ1OT1, LOC100270804, and FLJ10038 median levels were found to be significantly higher in the luminal subtype. The ROC plotter platform results showed that reduced expression of these three DElncRNAs was associated with breast cancer patients who did not respond to taxane treatment. Kaplan–Meier survival analysis revealed that a lower expression of the selected lncRNAs was significantly associated with worse relapse-free survival (RFS) in breast cancer patients. Further validation of the expression of these DELncRNAs might be helpful to better tailor breast cancer prognosis and treatment.

scholarly journals Investigating New Therapeutic Strategies Targeting Hyperinsulinemia's Mitogenic Effects in a Female Mouse Breast Cancer Model

Endocrinology ◽  
2013 ◽  
Vol 154 (5) ◽  
pp. 1701-1710 ◽  
Author(s):  
Ran Rostoker ◽  
Keren Bitton-Worms ◽  
Avishay Caspi ◽  
Zila Shen-Orr ◽  
Derek LeRoith
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Breast Tumor ◽  
Experimental Studies ◽  
Tumor Development ◽  
Treated Group ◽  
Tumor Growth Rate ◽  
Breast Cancer Patients ◽  
Mitogenic Effect

Abstract Epidemiological and experimental studies have identified hyperinsulinemia as an important risk factor for breast cancer induction and for the poor prognosis in breast cancer patients with obesity and type 2 diabetes. Recently it was demonstrated that both the insulin receptor (IR) and the IGF-IR mediate hyperinsulinemia's mitogenic effect in several breast cancer models. Although IGF-IR has been intensively investigated, and anti-IGF-IR therapies are now in advanced clinical trials, the role of the IR in mediating hyperinsulinemia's mitogenic effect remains to be clarified. Here we aimed to explore the potential of IR inhibition compared to dual IR/IGF-IR blockade on breast tumor growth. To initiate breast tumors, we inoculated the mammary carcinoma Mvt-1 cell line into the inguinal mammary fat pad of the hyperinsulinemic MKR female mice, and to study the role of IR, we treated the mice bearing tumors with the recently reported high-affinity IR antagonist-S961, in addition to the well-documented IGF-IR inhibitor picropodophyllin (PPP). Although reducing IR activation, with resultant severe hyperglycemia and hyperinsulinemia, S961-treated mice had significantly larger tumors compared to the vehicle-treated group. This effect maybe secondary to the severe hyperinsulinemia mediated via the IGF-1 receptor. In contrast, PPP by partially inhibiting both IR and IGF-IR activity reduced tumor growth rate with only mild metabolic consequences. We conclude that targeting (even partially) both IR and IGF-IRs impairs hyperinsulinemia's effects in breast tumor development while simultaneously sparing the metabolic abnormalities observed when targeting IR alone with virtual complete inhibition.

scholarly journals RT-PCR determination of maspin and mammaglobin B in peripheral blood of healthy donors and breast cancer patients

2006 ◽  
Vol 17 (3) ◽  
pp. 424-428 ◽  
Author(s):  
L. Mercatali ◽  
V. Valenti ◽  
D. Calistri ◽  
S. Calpona ◽  
G. Rosti ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Peripheral Blood ◽  
Breast Cancer Patients ◽  
Rt Pcr ◽  
Healthy Donors

scholarly journals Genotoxic and Cytotoxic Damage by Cyclophosphamide and Adriamycin as a Response to Treatment in Breast Cancer Patients: Pilot Study

2015 ◽  
Vol 06 (02) ◽  
pp. 163-168 ◽  
Author(s):  
Jimena Garibay-Garcia ◽  
Fernando Mejia-Sanchez ◽  
Eduardo Ramírez-San-Juan ◽  
Miriam V. Flores-Merino ◽  
Julieta Castillo-Cadena
Keyword(s):  
Breast Cancer ◽  
Pilot Study ◽  
Cancer Patients ◽  
Response To Treatment ◽  
Breast Cancer Patients

scholarly journals Sequential intra-arterial infusion of 90Y-resin microspheres and mitomycin C in chemo refractory liver metastatic breast cancer patients: a single centre pilot study

2020 ◽  
Vol 54 (1) ◽  
pp. 33-39
Author(s):  
Brigitte Maximiliana Aarts ◽  
Elisabeth Geneviève Klompenhouwer ◽  
Raphaëla Carmen Dresen ◽  
Christophe Michel Albert Louis Omer Deroose ◽  
Regina Gien Hoa Beets-Tan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Pilot Study ◽  
Mitomycin C ◽  
Progressive Disease ◽  
Metastatic Breast ◽  
Response To Treatment ◽  
Breast Cancer Patients ◽  
Arterial Infusion ◽  
Resin Microspheres

AbstractBackgroundThe aim of the study was to evaluate the safety and feasibility of intra-arterial mitomycin C (MMC) infusion after selective internal radiation therapy (SIRT) using Yttrium-90 (90Y) resin microspheres in liver metastatic breast cancer (LMBC) patients.Patients and methodsThe prospective pilot study included LMBC patients from 2012–2018. Patients first received infusion of 90Y resin microspheres, after 6–8 weeks response to treatment was assessed by MRI, 18F-FDG PET/CT and laboratory tests. After exclusion of progressive disease, MMC infusion was administrated 8 weeks later in different dose cohorts; A: 6 mg in 1 cycle, B: 12 mg in 2 cycles, C: 24 mg in 2 cycles and D: maximum of 72 mg in 6 cycles. In cohort D the response was evaluated after every 2 cycles and continued after exclusion of progressive disease. Adverse events (AE) were reported according to CTCAE version 5.0.ResultsSixteen patients received 90Y treatment. Four patients were excluded for MMC infusion, because of extra hepatic disease progression (n = 3) and clinical and biochemical instability (n = 1). That resulted in the following number of patient per cohort; A: 2, B: 1, C: 3 and D: 6. In 4 of the 12 patients (all cohort D) the maximum dose of MMC was adjusted due biochemical toxicities (n = 2) and progressive disease (n = 2). One grade 3 AE occurred after 90Y treatment consisting of a gastrointestinal ulcer whereby prolonged hospitalization was needed.ConclusionsSequential treatment of intra-arterial infusion of MMC after 90Y SIRT was feasible in 75% of the patients when MMC was administrated in different escalating dose cohorts. However, caution is needed to prevent reflux after 90Y SIRT in LMBC patients.

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