scholarly journals Breast tumor IGF-1R regulates cell adhesion and metastasis: Alignment of mouse single cell and human breast cancer transcriptomics

2021 ◽  
Author(s):  
Alison E Obr ◽  
Yung-Jun Chang ◽  
Virginia Ciliento ◽  
Alexander Lemenze ◽  
Krystopher Maingrette ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tyrosine Kinases ◽  
Immune Cell ◽  
Patient Survival ◽  
Patient Data ◽  
Critical Event ◽  
Breast Cancers ◽  
Human Breast ◽  
Metastatic Phenotype ◽  
Human Patient

The acquisition of a metastatic phenotype is the critical event that determines patient survival from breast cancer. Several receptor tyrosine kinases have functions both in promoting and inhibiting metastasis in breast tumors. Although the insulin-like growth factor 1 receptor (IGF-1R) has been considered a target for inhibition in breast cancer, low levels of IGF-1R expression are associated with worse overall patient survival. To determine how reduced IGF-1R impacts tumor phenotype, we used weighted correlation gene network analysis (WCGNA) of METABRIC patient data and identified gene modules specific to cell cycle, adhesion, and immune cell signaling inversely correlated with IGF-1R expression in human breast cancers. Integration of human patient data with data from mouse tumors revealed similar pathways necessary for promoting metastasis in basal-like tumors with reduced signaling or expression of the IGF-1R. Functional analyses revealed the basis for the enhanced metastatic phenotype including alterations in E- and P-cadherins.

scholarly journals MRCKα Is Dispensable for Breast Cancer Development in the MMTV-PyMT Model

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 942
Author(s):  
Mei Qi Kwa ◽  
Rafael Brandao ◽  
Trong H. Phung ◽  
Jianfeng Ge ◽  
Giuseppe Scieri ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression Signature ◽  
Genomic Analysis ◽  
Cancer Development ◽  
Breast Cancer Cell Lines ◽  
Normal Mammary Gland ◽  
Breast Cancers ◽  
Human Breast ◽  
Breast Cancer Development

MRCKα is a ubiquitously expressed serine/threonine kinase involved in cell contraction and F-actin turnover, which is highly amplified in human breast cancer and part of a gene expression signature for bad prognosis. Nothing is known about the in vivo function of MRCKα. To explore MRCKα function in development and in breast cancer, we generated mice lacking a functional MRCKα gene. Mice were born close to the Mendelian ratio and showed no obvious phenotype including a normal mammary gland formation. Assessing breast cancer development using the transgenic MMTV-PyMT mouse model, loss of MRCKα did not affect tumor onset, tumor growth and metastasis formation. Deleting MRCKα and its related family member MRCKβ in two triple-negative breast cancer cell lines resulted in reduced invasion of MDA-MB-231 cells, but did not affect migration of 4T1 cells. Further genomic analysis of human breast cancers revealed that MRCKα is frequently co-amplified with the oncogenes ARID4B and AKT3 which might contribute to the prognostic value of MRCKα expression. Collectively, these data suggest that MRCKα might be a prognostic marker for breast cancer, but probably of limited functional importance.

scholarly journals Extracellular Calcium-Sensing Receptor Expression and Its Potential Role in Regulating Parathyroid Hormone-Related Peptide Secretion in Human Breast Cancer Cell Lines*

Endocrinology ◽  
2000 ◽  
Vol 141 (12) ◽  
pp. 4357-4364 ◽  
Author(s):  
Jennifer L. Sanders ◽  
Naibedya Chattopadhyay ◽  
Olga Kifor ◽  
Toru Yamaguchi ◽  
Robert R. Butters ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Human Breast Cancer ◽  
Cancer Cell Lines ◽  
Human Breast Cancer Cell ◽  
Breast Cancer Cell Lines ◽  
Breast Cancers ◽  
Human Breast

Abstract Metastasis of breast cancer to bone occurs with advanced disease and produces substantial morbidity. Secretion of PTH-related peptide (PTHrP) from breast cancer cells is thought to play a key role in osteolytic metastases and is increased by transforming growth factor-β (TGFβ), which is released from resorbed bone. Elevated extracellular calcium (Cao2+) also stimulates PTHrP secretion from various normal and malignant cells, an action that could potentially be mediated by the Cao2+-sensing receptor (CaR) originally cloned from the parathyroid gland. Indeed, we previously showed that both normal breast ductal epithelial cells and primary breast cancers express the CaR. In this study we investigated whether the MCF-7 and MDA-MB-231 human breast cancer cell lines express the CaR and whether CaR agonists modulate PTHrP secretion. Northern blot analysis and RT-PCR revealed bona fide CaR transcripts, and immunocytochemistry and Western analysis with a specific anti-CaR antiserum demonstrated CaR protein expression in both breast cancer cell lines. Furthermore, elevated Cao2+ and the polycationic CaR agonists, neomycin and spermine, stimulated PTHrP secretion dose dependently, with maximal, 2.1- to 2.3-fold stimulation. In addition, pretreatment of MDA-MB-231 cells overnight with TGFβ1 (0.2, 1, or 5 ng/ml) augmented both basal and high Cao2+-stimulated PTHrP secretion. Thus, in PTHrP-secreting breast cancers metastatic to bone, the CaR could potentially participate in a vicious cycle in which PTHrP-induced bone resorption raises the levels of Cao2+ and TGFβ within the bony microenvironment, which then act in concert to evoke further PTHrP release and worsening osteolysis.

Profiling receptor tyrosine kinase fusions in Chinese breast cancers.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15092-e15092
Author(s):  
Zhonghua Tao ◽  
Xichun Hu ◽  
Wen-Ming Cao ◽  
Jianxia Liu ◽  
Ting Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tyrosine Kinase ◽  
Cancer Patients ◽  
Tyrosine Kinases ◽  
Breast Cancer Subtype ◽  
Stage Iv ◽  
Tyrosine Kinase Domain ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Her2 Positive

e15092 Background: Receptor tyrosine kinases (RTKs) are a class of tyrosine kinases that regulate cell-to-cell communication and control a variety of complex biological functions. Dysregulation of RTK signaling partly due to chromosomal rearrangements leads to novel tyrosine kinase fusion oncoproteins which are possibly driver alterations to cancers. Targeting some RTK fusions with specific tyrosine kinases inhibitors (TKIs) is an effective therapeutic strategy across a spectrum of RTK fusion-related cancers. However, there is still a paucity of extensive RTK fusion investigations in breast cancer. We aimed to characterize RTK fusions in Chinese breast cancer patients. Methods: An in-house sequencing database of 1440 Chinese breast cancer patients using a 520-gene NGS sequencing panel was thoroughly reviewed. RTK fusion was defined as an in-frame fusion with the tyrosine kinase domain of the RTK completely retained with the only exception of ERBB2 fusion which was not counted due to its unclear significance. Concomitant mutations and TMB were also analyzed and calculated. Patients’ clinical characteristics were retrieved from case records. Results: 27 RTK fusion-positive breast cancers (12 tissues + 15 plasmas) were identified, patients had a median age of 52 years. Triple-negative breast cancer subtype comprised 37% with luminal and HER2 positive subtypes being 40.8% and 22.2%, respectively. 77.8% of patients were at stage IV and 22.2% at stage I-III. Ten were treatment naïve. RTK fusions occurred in 2% of breast cancers in our database, compared with the prevalence of 0.6% and 1.3% in MSKCC and TCGA, respectively. In the subset of stage IV patients, our database showed a significantly higher RTK fusion frequency than that in MSKCC (3.2% vs. 0.6%, p = 0.013). FGFR2 fusions were seen most commonly (n = 7), followed by RET (n = 4), ROS1 (n = 3), NTRK3 (n = 3), BRAF (n = 2), and NTRK1 (n = 2). Other RTK fusions including ALK, EGFR, FGFR1, FGFR3, MET, and NTRK2 were identified in one patient each. Of note, the normalized abundance of RTK fusion (fusion AF/max AF) correlated negatively with TMB (r = -0.48, p = 0.017). Patients with TMB < 4 (Muts/Mb) displayed a higher fusion abundance than those with TMB ≥ 4 (Muts/Mb) (p = 0.018), suggesting a higher likelihood of subclonal nature for RTK fusions in TMB-high patients. Moreover, CREBBP mutation only co-occurred with FGFR2 fusion (p = 0.012), while NTRK3 fusion and TP53 mutation were mutually exclusive (p = 0.019). Conclusions: This is the first study comprehensively delineating the prevalence and spectrum of RTK fusions in Chinese breast cancers. Further study is ongoing to identify the enriched subpopulation which may benefit from RTK fusion inhibitors.

scholarly journals Tumor suppressive function of Matrin 3 in the basal-like breast cancer

2020 ◽  
Vol 53 (1) ◽  
Author(s):  
Jaehyuk Yang ◽  
Seung Jun Lee ◽  
Yongseok Kwon ◽  
Li Ma ◽  
Jongchan Kim
Keyword(s):  
Breast Cancer ◽  
Human Breast Cancer ◽  
Patient Survival ◽  
Apoptotic Cell ◽  
Migration And Invasion ◽  
Breast Cancer Patients ◽  
Human Breast ◽  
Basal Like Breast Cancer ◽  
Tumor Suppressive Function

Abstract Background Basal-like breast cancer (BLBC) or triple-negative breast cancer (TNBC) is an aggressive and highly metastatic subtype of human breast cancer. The present study aimed to elucidate the potential tumor-suppressive function of MATR3, an abundant nuclear protein, in BLBC/TNBC, whose cancer-relevance has not been characterized. Methods We analyzed in vitro tumorigenecity by cell proliferation and soft agar colony formation assays, apoptotic cell death by flow cytometry and Poly (ADP-ribose) polymerase (PARP) cleavage, epithelial-mesenchymal transition (EMT) by checking specific EMT markers with real-time quantitative PCR and in vitro migration and invasion by Boyden Chamber assays. To elucidate the underlying mechanism by which MATR3 functions as a tumor suppressor, we performed Tandem affinity purification followed by mass spectrometry (TAP-MS) and pathway analysis. We also scrutinized MATR3 expression levels in the different subtypes of human breast cancer and the correlation between MATR3 expression and patient survival by bioinformatic analyses of publicly available transcriptome datasets. Results MATR3 suppressed in vitro tumorigenecity, promoted apoptotic cell death and inhibited EMT, migration, and invasion in BLBC/TNBC cells. Various proteins regulating apoptosis were identified as MATR3-binding proteins, and YAP/TAZ pathway was suppressed by MATR3. MATR3 expression was inversely correlated with the aggressive and metastatic nature of breast cancer. Moreover, high expression levels of MATR3 were associated with a good prognosis of breast cancer patients. Conclusions Our data demonstrate that MATR3 functions as a putative tumor suppressor in BLBC/TNBC cells. Also, MATR3 potentially plays a role as a biomarker in predicting chemotherapy-sensitivity and patient survival in breast cancer patients.

scholarly journals Characterization of organoid cultured human breast cancer

2019 ◽  
Vol 21 (1) ◽  
Author(s):  
Nadine Goldhammer ◽  
Jiyoung Kim ◽  
Vera Timmermans-Wielenga ◽  
Ole William Petersen
Keyword(s):  
Breast Cancer ◽  
Primary Breast Cancer ◽  
Human Breast Cancer ◽  
Breast Cancers ◽  
Basal Cells ◽  
Human Breast ◽  
Contemporary Culture ◽  
Mucin 1 ◽  
Organoid Cultures ◽  
Primary Human Breast

AbstractOrganoid cultures are increasingly used to model human cancers experimentally with a view to tailoring personalized medicine and predicting drug responses. Breast cancer is no exception, but in particular, primary breast cancer poses some inherent difficulties due to the frequent presence of residual non-malignant cells in the biopsies. We originally developed an assay for the distinction between malignant and non-malignant structures in primary breast cancer organoid cultures (Petersen et al., Proc Natl Acad Sci (USA) 89(19):9064–8, 1992). Here, we apply this assay to assess the frequency of normal-like organoids in primary breast carcinoma cultures and the cellular composition as a consequence of passaging. We find that in consecutively collected samples of primary human breast cancers, residual non-malignant tissues were observed histologically in five out of ten biopsies. Based on relevant morphogenesis and correct polarization as recorded by expression in luminal epithelial cells of mucin 1 (Muc1), occludin, and keratin 19 (K19) and expression in basal cells of integrin β4, p63, and K14, non-malignant organoids were present in all primary human breast cancer-derived cultures. Furthermore, passaging in a contemporary culture medium was in favor of the selective expansion of basal-like cells. We conclude that organoid cultures of human breast cancers are most representative of the tissue origin in primary culture.

Assessment of Methods for Tissue-Based Detection of the HER-2/neu Alteration in Human Breast Cancer: A Direct Comparison of Fluorescence In Situ Hybridization and Immunohistochemistry

2000 ◽  
Vol 18 (21) ◽  
pp. 3651-3664 ◽  
Author(s):  
Giovanni Pauletti ◽  
Suganda Dandekar ◽  
HongMei Rong ◽  
Lilllian Ramos ◽  
HongJun Peng ◽  
...  
Keyword(s):  
Breast Cancer ◽  
In Situ Hybridization ◽  
Fluorescence In Situ Hybridization ◽  
Gene Amplification ◽  
Survival Probability ◽  
Human Breast Cancer ◽  
Patient Survival ◽  
Human Breast ◽  
Her 2

PURPOSE: To compare the efficacy of fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) in detecting the HER-2/neu alteration in human breast cancer. PATIENTS AND METHODS: Unselected stage I, II, and III breast cancer patients (N = 900) were tested for HER-2/neu gene amplification by FISH in paraffin-embedded, formalin-fixed archival material. Of these samples, 856 were tested for HER-2/neu overexpression by non–antigen-retrieval IHC with the polyclonal antibody R60, the sensitivity and specificity of which was preliminarily compared with the United States Food and Drug Administration–approved HercepTest (Dako Corp, Carpinteria, CA). Patient survival was analyzed in relation to the presence of the HER-2/neu alteration as determined by these two methodologies. RESULTS: A total of 189 (21%) of 900 patients were positive by FISH and 147 (17.2%) of 856 were positive by IHC. This discrepancy is consistent with expected loss of IHC sensitivity associated with tissue fixation/embedding. The HercepTest did not improve sensitivity and introduced false positives. Comparison of R60-based IHC with FISH demonstrates that patient survival is associated progressively to gene amplification level as determined by FISH, whereas for IHC an association is found only in the highest (3+) immunostaining group. Among FISH-negative tumors, 45 (6.6%) of 678 were IHC-positive, with a survival probability similar to that of FISH-negative/IHC-negative cases; FISH-positive/IHC-negative patients have a survival probability similar to that of FISH-positive/IHC-positive cases. CONCLUSION: IHC does not consistently discriminate patients likely to have a poor prognosis, whereas FISH provides superior prognostic information in segregating high-risk from lower-risk beast cancers. HER-2/neu protein overexpression in the absence of gene amplification occurs infrequently in breast cancer, in which case, patient outcome is similar to that of patients without the alteration.

Immunohistochemical Study of Ten Cases of Argyrophilic Carcinoma (Carcinoid) of the Breast

1988 ◽  
Vol 74 (3) ◽  
pp. 295-302 ◽  
Author(s):  
Salvatore Andreola ◽  
Emanuela Di Re ◽  
Mirella Merson ◽  
Lorenza Maggiulli ◽  
Patrizia De Palma
Keyword(s):  
Breast Cancer ◽  
Natural History ◽  
Human Breast Cancer ◽  
Immunohistochemical Study ◽  
Secretory Activity ◽  
Controversial Issue ◽  
Breast Cancers ◽  
Human Breast ◽  
History Of

The significance of argyrophilia in human breast cancer is still a controversial issue. We tested immunohistochemically 10 cases of argyrophilic carcinomas of the breast and found evidence of immunoreactivity with neuroendocrine markers: chromogranin, NSE, gastrin, insulin and bombesin. Argyrophilia was demonstrated in breast cancers of the usual types and was found to be related to the secretory activity of neoplastic cells. Unfortunately, no adequate follow-up data are available to clarify the natural history of argyrophilic breast cancer. A clinical treatment different from that of conventional breast cancer is not at present justified.

scholarly journals Somatic Mutation of PIK3CA (H1047R) Is a Common Driver Mutation Hotspot in Canine Mammary Tumors as Well as Human Breast Cancers

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 2006 ◽  
Author(s):  
Kang-Hoon Lee ◽  
Hyeon-Ji Hwang ◽  
Hyun Ji Noh ◽  
Tae-Jin Shin ◽  
Je-Yoel Cho
Keyword(s):  
Breast Cancer ◽  
Human Cancer ◽  
Association Studies ◽  
Cell Metabolism ◽  
Driver Mutations ◽  
Genome Wide Association Studies ◽  
Breast Cancers ◽  
Human Breast ◽  
Normal Tissues ◽  
Whole Exome

Breast cancer is one of the most frequently diagnosed cancers in both women and female dogs. Genome-wide association studies in human breast cancer (HBC) have identified hundreds of genetic variations and somatic driver mutations. However, only a handful of variants have been studied for rare HBC and their associations remain inconclusive. Spontaneous canine mammary tumor (CMT) is a great model for HBC, with clinical similarity. We thus performed whole-exome sequencing in 20 pairs of CMT and normal tissues in dogs. We newly found that PIK3CA was the most frequently mutated gene in CMT (45%). Furthermore, canine PIK3CA A3140G (H1047R), at what is known as the mutational hotspot of HBC, is also a hotspot in CMT. Targeted sequencing confirmed that 29% of CMTs had the same PIK3CA A3140G mutation. Integration of the transcriptome suggests that the PIK3CA (H1047R) induced cell metabolism and cell cycle via an increase of PCK2 and a decrease of CDKN1B but had no effect on cell apoptosis. We identified additional significantly mutated genes, including SCRN1 and CLHC1, which have not been reported in HBC. Our study recapitulated some known HBC-associated genes and human cancer signatures in CMT, and identified novel genes that may be relevant to HBC. This study may allow us to better understand both HBC and CMT and lend new insights into the development of biomarkers.

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