scholarly journals Mice developing mammary tumors evolve T cell sequences shared with human breast cancer patients

2018 ◽  
Author(s):  
Miri Gordin ◽  
Hagit Philip ◽  
Alona Zilberberg ◽  
Moriah Gidoni ◽  
Raanan Margalit ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
T Cell ◽  
Cancer Patients ◽  
Human Breast Cancer ◽  
Tumor Development ◽  
Mammary Tumors ◽  
Cell Receptor ◽  
Breast Cancer Patients ◽  
Human Breast

AbstractCancer immunotherapy by checkpoint blockade proves that an effective immune response to a tumor can be induced clinically. However, little is known about the evolution of tumor-associated T-cell receptor (TCR) repertoires without intervention. Here we studied TCR repertoire evolution in mice spontaneously developing mammary tumors; we sequenced peripheral blood alpha and beta TCRs of CD4+CD62L+CD44− T cells monthly for 8 months in 10 FVB/NJ mice transgenic at the Erbb2 locus, all developing tumors; 5 FVB/NJ mice without the transgene were age-matched controls. Sequences were either private (restricted to one mouse) or public (shared among mice); public sequences were either exclusive to the tumor group or inclusive among different groups. We now report that 1), public AA sequences were each encoded by many different nucleotide sequences (NT) recombinations (convergent recombination; CR); 2) mice developing tumors evolved tumor-exclusive public sequences, derived initially from private or from inclusive public sequences; and 3) tumor-exclusive public sequences in mice were also present among published public TCR sequences from human breast cancer patients. These cross-species tumor-exclusive TCR sequences manifested high CR; but the AA sequences shared by mice and humans did not share NT sequences. Thus, tumor-exclusive TCR AA sequences across species are selected from different NT recombination events. The roles of tumor-exclusive TCR repertoires in advancing or inhibiting tumor development and the effects of tumor immunotherapy on these T cells remain to be seen.

scholarly journals Diagnostic and Prognostic implications of AAGAB expression in human breast cancer

2020 ◽  
Author(s):  
Cheng Zhang ◽  
Chen Gong ◽  
Yang Liu ◽  
Changcai Wang ◽  
Cheng Zeng ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Cancer Patients ◽  
Human Breast Cancer ◽  
Univariate Analysis ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Breast Cancer Patients ◽  
Human Breast ◽  
Poor Overall Survival

Abstract Background: Alpha and gamma adaptin binding protein p34 (AAGAB) was previously reported as a novel on-treatment biomarker can improve prediction of response to neoadjuvant chemotherapy in breast cancer. However, the expression and prognostic value of AAGAB in breast cancer is unknown, the function of AAGAB in breast cancer remains to be elucidated. Methods: Herein we investigated the role of AAGAB in human breast cancer from the TCGA database, immunohistochemistry, Gene set enrichment analysis (GSEA) and immune infiltration analysis. Results: Increased AABAB expression in breast cancer was significantly associated with age, gender, race, ER status, PR status, N-stage, PAM50 classification and histological type (all p-values<0.05). Kaplan-Meier survival analysis showed that breast cancer patients with AAGAB-high had a worse prognosis than that with AAGAB-low (p=0.005). Univariate analysis using logistic regression revealed that age, pathological stage, and number of lymph nodes were significantly associated with poor overall survival (OS) (all p <0.05). AAGAB expression level was significantly correlated with cell purity, CD8 T cells, macrophages, CD4 T cells and dendritic cells. Functional annotations indicated that AAGAB is involved in the most significant signaling pathways including intra Golgi traffic and peroxisomal lipid metabolism pathways. Conclusions: Our study revealed that elevated AAGAB expression was significantly correlated with aggressive progression, poor survival in breast cancer patients. AAGAB may serve as a new biomarker and potential treatment target in breast cancer.

scholarly journals Antiestrogen-resistant human breast cancer cells require activated Protein Kinase B/Akt for growth

2005 ◽  
Vol 12 (3) ◽  
pp. 599-614 ◽  
Author(s):  
T Frogne ◽  
J S Jepsen ◽  
S S Larsen ◽  
C K Fog ◽  
B L Brockdorff ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Cell Lines ◽  
Human Breast Cancer ◽  
Neutralizing Antibodies ◽  
Breast Cancer Cells ◽  
Resistant Cell ◽  
Breast Cancer Patients ◽  
Human Breast ◽  
Mcf 7

Development of acquired resistance to antiestrogens is a major clinical problem in endocrine treatment of breast cancer patients. The IGF system plays a profound role in many cancer types, including breast cancer. Thus, overexpression and/or constitutive activation of the IGF-I receptor (IGF-IR) or different components of the IGF-IR signaling pathway have been reported to render breast cancer cells less estrogen dependent and capable of sustaining cell proliferation in the presence of antiestrogens. In this study, growth of the antiestrogen-sensitive human breast cancer cell line MCF-7 was inhibited by treatment with IGF-IR-neutralizing antibodies. In contrast, IGF-IR-neutralizing antibodies had no effect on growth of two different antiestrogen-resistant MCF-7 sublines. A panel of antiestrogen-resistant cell lines was investigated for expression of IGF-IR and either undetectable or severely reduced IGF-IR levels were observed. No increase in insulin receptor substrate 1 (IRS-1) or total PKB/Akt (Akt) was detected in the resistant cell lines. However, a significant increase in phosphorylated Akt (pAkt) was found in four of six antiestrogen-resistant cell lines. Overexpression of pAkt was associated with increased Akt kinase activity in both a tamoxifen- and an ICI 182,780-resistant cell line. Inhibition of Akt phosphorylation by the phosphatidylinositol 3-kinase (PI3-K) inhibitor wortmannin or the Akt inhibitor SH-6 (structurally modified phosphatidyl inositol ether liquid analog PIA 6) resulted in a more pronounced growth inhibitory effect on the antiestrogen-resistant cells compared with the parental cells, suggesting that signaling via Akt is required for antiestrogen-resistant cell growth in at least a subset of our antiestrogen-resistant cell lines. PTEN expression and activity was not decreased in cell lines overexpressing pAkt. Our data demonstrate that Akt is a target for treatment of antiestrogen-resistant breast cancer cell lines and we suggest that antiestrogen-resistant breast cancer patients may benefit from treatment targeted to inhibit Akt signaling.

Tumor immune microenvironment (TiME) changes by multiplex IF staining in a pilot study of neoadjuvant talazoparib for early-stage breast cancer patients with a BRCA mutation.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 585-585
Author(s):  
Evthokia Hobbs ◽  
Fei Yang ◽  
Tapsi Kumar ◽  
Alejandro Contreras ◽  
Edwin Roger Parra Cuentas ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
T Cell ◽  
Cancer Patients ◽  
Early Stage ◽  
Post Treatment ◽  
Early Stage Breast Cancer ◽  
Parp Inhibition ◽  
Cytotoxic T Cell ◽  
Breast Cancer Patients

585 Background: We previously reported a median tumor volume loss of 88% (range 30-98%) in 13 patients with early stage BRCA1/2 mutant breast cancer treated on a neoadjuvant trial of the PARP inhibitor talazoparib. The effects of PARP inhibition on immune aspects of the TiME in early-stage breast cancer has not been well described. The goal of this study was to evaluate the TiME in pre and post-treatment core biopsies from enrolled patients. Methods: Eleven paired core biopsies were available for examination. Tumor infiltrating lymphocytes (TILs) were quantified by H&E stained slides by a central pathologist. Specimens were assessed by multiplex immunofluorescence (mIF) using a panel of 6 biomarkers (PD-1, PD-L1, CD3, CD8, CD68 and CK) with the Opal 7-color Kit in LEICA BOND auto stainer, Vectra automated quantitative pathology imaging system and inForm software (PerkinElmer). Results: In the analyzed core biopsies, there was an increase in TILs evaluated by H&E in post-treatment compared to baseline (mean 36 vs 11%). By mIF there was an increase in CD3+ T cell and CD3+CD8+ cytotoxic T cell density in post-treatment samples compared to baseline, summarized in table. PD-L1 expression in tumor cells was rare in the cohort. There was no difference in CD3+PD-1+ or CD3+CD8+ PD-1+ lymphocytes in pre and post-treatment specimens. There was also no differences in macrophages (CD68+). Evaluation of immune phenotype and imaging response will be presented in the final analysis. Conclusions: This is the first study phenotyping the immune response to neoadjuvant talazoparib in BRCA-mutant breast cancer patients. In this small cohort, intratumoral and stromal CD3+ T cells and CD3+CD8+ cytotoxic T cells increased after two months of talazoparib. Clinical trial information: NCT02282345. [Table: see text]

The Hedgehog signalling pathway mediates drug response of MCF-7 mammosphere cells in breast cancer patients

2015 ◽  
Vol 129 (9) ◽  
pp. 809-822 ◽  
Author(s):  
Miao He ◽  
Yingzi Fu ◽  
Yuanyuan Yan ◽  
Qinghuan Xiao ◽  
Huizhe Wu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Human Breast Cancer ◽  
Drug Response ◽  
Breast Cancer Patients ◽  
Human Breast ◽  
Hedgehog Signalling ◽  
Hedgehog Signalling Pathway ◽  
Xenograft Mice ◽  
Mcf 7

Our study showed that Hh signalling activation contributed to BCSC-mediated chemoresistance in cultured breast cancer MCF-7 MS cells, in xenograft mice and in human breast cancer patients.

scholarly journals TMEM71 expression associates with survival in triple negative breast cancer.

2021 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Triple Negative Breast Cancer ◽  
Human Breast Cancer ◽  
Triple Negative ◽  
Transmembrane Protein ◽  
Breast Cancer Patients ◽  
Human Breast ◽  
Primary Tumors ◽  
Significant Gene

We mined published microarray data (1) to understand the most significant gene expression differences in the tumors of triple negative breast cancer patients based on survival following treatment: dead or alive. We observed significant transcriptome-wide differential expression of transmembrane protein 71, encoded by TMEM71 when comparing the primary tumors of triple negative breast cancer patients dead or alive. Importantly, TMEM71 expression was correlated with overall survival in patients with human breast cancer. TMEM71 may be of relevance as a biomarker or as a molecule of interest in understanding the etiology or progression of triple negative breast cancer.

scholarly journals Increased Soluble CrkL in Serum of Breast Cancer Patients Is Associated with Advanced Disease

Cancers ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 961 ◽  
Author(s):  
Srimeenakshi Srinivasan ◽  
Biana Godin
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Cell Lines ◽  
Breast Cancer Cell ◽  
Human Breast Cancer ◽  
Advanced Disease ◽  
Human Breast Cancer Cell ◽  
Breast Cancer Cell Lines ◽  
Breast Cancer Patients ◽  
Human Breast

Over-expression of Crk-like protein (CrkL), an intracellular adaptor protein, in breast cancer biopsies has been linked to poor prognosis. CrkL can be secreted from cancer cells binding to β1 integrin on the cell membrane. In this study, we evaluated, for the first time, the levels of soluble CrkL in serum of breast cancer patients. Expression of CrkL and secreted fractions from human breast cancer cell lines and clinical patient samples were assessed by immunohistochemistry and Enzyme Linked Immuno-Sorbent Assay (ELISA). CrkL levels in tissues and sera of patients with different disease stages were compared and statistically analyzed by Chi-square test and Student’s t-test. Culture media from human breast cancer cell lines SUM159, MDA-MB231, and MCF7 showed over a 21-, 15-, and 11-fold higher concentration of soluble CrkL as compared to normal breast epithelium cell line MCF10A. Expression of CrkL was elevated in 85% of breast tumor tissue sections. Serum levels of CrkL were significantly higher in breast cancer patients than in healthy donors. All patients with metastatic disease had significantly elevated concentration of soluble CrkL in the serum with on average three-fold increase from the baseline. The data suggest that soluble fraction of CrkL can be further evaluated as a serum biomarker for advanced disease in breast cancer patients.

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