scholarly journals Disruption of STAT5A and NMI signaling axis leads to ISG20-driven metastatic mammary tumors

Oncogenesis ◽  
2021 ◽  
Vol 10 (6) ◽  
Author(s):  
Heba Allah M. Alsheikh ◽  
Brandon J. Metge ◽  
Hawley C. Pruitt ◽  
Sarah C. Kammerud ◽  
Dongquan Chen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Metastatic Breast ◽  
Mammary Tumors ◽  
Mammary Development ◽  
Primary Breast Tumor ◽  
Metastatic Progression ◽  
Breast Cancer Patients ◽  
Primary Tumors ◽  
Cancer Initiation

AbstractMolecular dynamics of developmental processes are repurposed by cancer cells to support cancer initiation and progression. Disruption of the delicate balance between cellular differentiation and plasticity during mammary development leads to breast cancer initiation and metastatic progression. STAT5A is essential for differentiation of secretory mammary alveolar epithelium. Active STAT5A characterizes breast cancer patients for favorable prognosis. N-Myc and STAT Interactor protein (NMI) was initially discovered as a protein that interacts with various STATs; however, the relevance of these interactions to normal mammary development and cancer was not known. We observe that NMI protein is expressed in the mammary ductal epithelium at the onset of puberty and is induced in pregnancy. NMI protein is decreased in 70% of patient specimens with metastatic breast cancer compared to primary tumors. Here we present our finding that NMI and STAT5A cooperatively mediate normal mammary development. Loss of NMI in vivo caused a decrease in STAT5A activity in normal mammary epithelial as well as breast cancer cells. Analysis of STAT5A mammary specific controlled genetic program in the context of NMI knockout revealed ISG20 (interferon stimulated exonuclease gene 20, a protein involved in rRNA biogenesis) as an unfailing negatively regulated target. Role of ISG20 has never been described in metastatic process of mammary tumors. We observed that overexpression of ISG20 is increased in metastases compared to matched primary breast tumor tissues. Our observations reveal that NMI-STAT5A mediated signaling keeps a check on ISG20 expression via miR-17–92 cluster. We show that uncontrolled ISG20 expression drives tumor progression and metastasis.

scholarly journals DVL3 is over-expressed in the tumors of breast cancer patients treated with trastuzumab.

2020 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Growth Factor Receptor ◽  
Metastatic Breast ◽  
The United States ◽  
Breast Cancer Patients ◽  
Gene Encoding ◽  
Significant Differential Expression ◽  
Primary Tumors ◽  
Unbiased Manner

Trastuzumab (Herceptin) is a monoclonal antibody targeting the extracellular domain of the human epidermal growth factor receptor 2 (HER2) (1) utilized for the treatment of adjuvant and metastatic breast cancer (2) in the United States and worldwide. We mined published and public microarray and gene expression data (3, 4) to discover in an unbiased manner the most striking transcriptional features of trastuzumab treatment. We identified significant differential expression of the gene encoding the Wnt pathway molecule dishevelled-3, DVL3 (5-7), in the primary tumors of breast cancer patients treated with trastuzumab. DVL3 expression in primary tumors of the breast in patients treated with trastuzumab was significantly higher than in patients not treated with trastuzumab.

scholarly journals DCC is differentially expressed in the tumors of breast cancer patients treated with trastuzumab.

2020 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Messenger Rna ◽  
Growth Factor Receptor ◽  
Metastatic Breast ◽  
The United States ◽  
Differentially Expressed ◽  
Breast Cancer Patients ◽  
Primary Tumors ◽  
Deleted In Colorectal Cancer

Trastuzumab (Herceptin) is a monoclonal antibody targeting the extracellular domain of the human epidermal growth factor receptor 2 (HER2) (1) utilized for the treatment of adjuvant and metastatic breast cancer (2) in the United States and worldwide. We mined published microarray and gene expression data (3, 4) to discover in an unbiased manner the most striking transcriptional features of trastuzumab treatment. We identified the deleted in colorectal cancer locus DCC (5, 6) as among the genes most differentially expressed in the primary tumors of patients with breast cancer treated with trastuzumab. The primary tumors of breast cancer patients treated with trastuzumab expressed higher levels of DCC messenger RNA than did patients not treated with trastuzumab, and a single administration of trastuzumab was sufficient to result in differential expression of DCC in primary tumors of the breast, demonstrating that a gene encoding for a netrin receptor, cellular machinery utilized for axon guidance in the central nervous system (5-9), is transcriptionally induced in primary tumors of the breast following treatment with trastuzumab.

scholarly journals Myelin transcription factor 1 (MYT1) is differentially expressed in the tumors of breast cancer patients treated with trastuzumab.

2020 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Breast Cancer ◽  
Transcription Factor ◽  
Cancer Patients ◽  
Messenger Rna ◽  
Metastatic Breast ◽  
The United States ◽  
Differentially Expressed ◽  
Breast Cancer Patients ◽  
Primary Tumors ◽  
Transcription Factor 1

Trastuzumab (Herceptin) is a monoclonal antibody targeting the extracellular domain of the human epidermal growth factor receptor 2 (HER2) (1) utilized for the treatment of adjuvant and metastatic breast cancer (2) in the United States and worldwide. We mined published microarray and gene expression data (3, 4) to discover in an unbiased manner the most significant transcriptional changes associated with trastuzumab treatment. We identified myelin transcription factor 1, encoded by MYT1 among the genes most differentially expressed in the primary tumors of patients with breast cancer treated with trastuzumab. The primary tumors of breast cancer patients treated with trastuzumab expressed higher levels of MYT1 messenger RNA than did patients not treated with trastuzumab, and a single administration of trastuzumab was sufficient to result in differential expression of MYT1 in primary tumors of the breast, demonstrating increased expression of a zinc finger DNA-binding protein and neuronal-specific members of the LSD1 complex with the capacity to interact with Sin3B and with functions in neurogenesis (5-9) as a direct transcriptional consequence of treatment with trastuzumab.

scholarly journals S100A4 released from highly bone-metastatic breast cancer cells plays a critical role in osteolysis

Bone Research ◽  
2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Haemin Kim ◽  
Bongjun Kim ◽  
Sang Il Kim ◽  
Hyung Joon Kim ◽  
Brian Y. Ryu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Bone Metastasis ◽  
Bone Loss ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Cancer Metastasis ◽  
Critical Role ◽  
Bone Destruction ◽  
Metastatic Breast ◽  
Breast Cancer Patients

Abstract Bone destruction induced by breast cancer metastasis causes severe complications, including death, in breast cancer patients. Communication between cancer cells and skeletal cells in metastatic bone microenvironments is a principal element that drives tumor progression and osteolysis. Tumor-derived factors play fundamental roles in this form of communication. To identify soluble factors released from cancer cells in bone metastasis, we established a highly bone-metastatic subline of MDA-MB-231 breast cancer cells. This subline (mtMDA) showed a markedly elevated ability to secrete S100A4 protein, which directly stimulated osteoclast formation via surface receptor RAGE. Recombinant S100A4 stimulated osteoclastogenesis in vitro and bone loss in vivo. Conditioned medium from mtMDA cells in which S100A4 was knocked down had a reduced ability to stimulate osteoclasts. Furthermore, the S100A4 knockdown cells elicited less bone destruction in mice than the control knockdown cells. In addition, administration of an anti-S100A4 monoclonal antibody (mAb) that we developed attenuated the stimulation of osteoclastogenesis and bone loss by mtMDA in mice. Taken together, our results suggest that S100A4 released from breast cancer cells is an important player in the osteolysis caused by breast cancer bone metastasis.

scholarly journals Periodontal inflammation recruits distant metastatic breast cancer cells by increasing myeloid-derived suppressor cells

Oncogene ◽  
2019 ◽  
Vol 39 (7) ◽  
pp. 1543-1556 ◽  
Author(s):  
Ran Cheng ◽  
Sandrine Billet ◽  
Chuanxia Liu ◽  
Subhash Haldar ◽  
Diptiman Choudhury ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Progression ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Breast Cancer Cells ◽  
Periodontal Diseases ◽  
Metastatic Breast ◽  
Metastatic Progression ◽  
Premetastatic Niche ◽  
Periodontal Inflammation

Abstract Periodontal diseases can lead to chronic inflammation affecting the integrity of the tooth supporting tissues. Recently, a striking association has been made between periodontal diseases and primary cancers in the absence of a mechanistic understanding. Here we address the effect of periodontal inflammation (PI) on tumor progression, metastasis, and possible underlining mechanisms. We show that an experimental model of PI in mice can promote lymph node (LN) micrometastasis, as well as head and neck metastasis of 4T1 breast cancer cells, both in early and late stages of cancer progression. The cervical LNs had a greater tumor burden and infiltration of MDSC and M2 macrophages compared with LNs at other sites. Pyroptosis and the resultant IL-1β production were detected in patients with PI, mirrored in mouse models. Anakinra, IL-1 receptor antagonist, limited metastasis, and MDSC recruitment at early stages of tumor progression, but failed to reverse established metastatic tumors. PI and the resulting production of IL-1β was found to promote CCL5, CXCL12, CCL2, and CXCL5 expression. These chemokines recruit MDSC and macrophages, finally enabling the generation of a premetastatic niche in the inflammatory site. These findings support the idea that periodontal inflammation promotes metastasis of breast cancer by recruiting MDSC in part by pyroptosis-induced IL-1β generation and downstream CCL2, CCL5, and CXCL5 signaling in the early steps of metastasis. These studies define the role for IL-1β in the metastatic progression of breast cancer and highlight the need to control PI, a pervasive inflammatory condition in older patients.

Patterns of HER2/neu, hormonal receptor expression, and proliferative activity in primary and metastatic breast cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 1071-1071
Author(s):  
F. Giotta ◽  
G. Simone ◽  
V. Fazio ◽  
S. Longo ◽  
S. Petroni ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Predictive Factors ◽  
Proliferative Activity ◽  
Metastatic Breast ◽  
Receptor Expression ◽  
Breast Cancer Patients ◽  
Primary Tumors ◽  
Prognostic And Predictive Factors ◽  
Mib 1

1071 Background: The modification of biological features of metastatic sites (MS) in breast cancer patients arise some debatable questions regarding clinically usefull information and safe/efficient methods to detect them. Fine needle aspiration (FNA) of visceral MS is an available tool to characterize tumoral lesion and liquid based citology technique provides usefull cell samples for immunocytochemical and/or molecular assays. Methods: The aim of this study was to compare prognostic and predictive factors obtained from primary tumors (PT) and corresponding MS. Fluorescent in situ hybridization (FISH) was performed for HER2/Neu determination, while ER, PgR, and MIB-1 were detected by immunochemistry using specific monoclonal antibodies on monolayered cell sample and in the corresponding cytoinclusion. FNA with a 21–23 G needle was performed in 20 consecutive breast cancer patients with distant metacronous MS. Results: In 8/20 patients, both ER and PgR were absent in PT and in MS, in 7 were both present, in 4 cases only ER was detected, and only 1 case was ER negative with a low PgR. About the proliferative activity (MIB-1 index: cut off value >20%) only 3 MS presented an higher value. With regard to HER2/Neu, 4/20 cases were amplified and no discrepancies were found between cytological and cytoinclusion specimens. No substantial changes were found about kinetic activity. HER2/Neu status as assessed in PT was confirmed in MS in 10/12 cases; a lung mestastasis showed amplification while primary was not amplified and a liver lesion lost the amplification which was detected in the PT. Conclusions: Our study strongly suggest the opportunity in using FNA for detection of prognostic and predictive factors in MS. Pectasides et al. (Anticancer Res. 2006) found in patients with altered or conserved HER2/Neu in PT and in MS different response rates between the two groups and a significant poorer prognosis in patients with altered Neu. We think that liquid-based cytology applied on FNA of distant metastases could help us to understand some more in this issue. No significant financial relationships to disclose.

Capture of EpCAM-negative and vimentin-positive circulating cancer cells (CCCs) from blood of metastatic breast cancer patients using ApoStream.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e21029-e21029
Author(s):  
Christopher Neal ◽  
Sujita Sukumaran ◽  
Vishal Gupta ◽  
Insiya Jafferji ◽  
Dave Hasegawa ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Cancer Progression ◽  
Laser Scanning ◽  
Metastatic Breast ◽  
Breast Cancer Patients ◽  
Mesenchymal Transition ◽  
Circulating Cancer Cells

e21029 Background: Up-regulation of epithelial mesenchymal transition (EMT) and the reduction of epithelial marker expression is associated with invasion, cancer progression, resistance to conventional therapies and poor prognosis. ApoStream, a novel continuous flow dielectrophoresis field-flow fractionation (DEP-FFF) device, was used to enable antibody-independent capture of circulating cancer cells (CCCs,also referred to as circulating tumor cells, CTC) for subsequent phenotyping of EMT markers. Methods: A side-by-side comparison of CellSearch and ApoStream was performed on 10 metastatic breast cancer patients. A multiplexed immunofluorescent assay and laser scanning cytometry analyses were used to unambiguously identify CK+/CD45–/DAPI+ CCCs and quantify their EpCAM and vimentin expression. Results: ApoStream recovered CK+/CD45–/DAPI+ CCCs from each breast cancer patient sample tested (mean=255 CCCs per 7.5 ml blood, see Table). ApoStream consistently recovered significantly higher number of CCCs compared to CellSearch (p=0.024). ApoStream recovered both EpCAM+ and EpCAM– CCCs in 50% and 90% of patients, respectively. Vimentin+ CCCs were isolated from 90% of patients. Conclusions: ApoStream’s higher capture efficiency demonstrated the majority of CCCs from breast cancer patients were EpCAM negative and vimentin-positive. ApoStream technology can be used to monitor CCCs undergoing EMT. [Table: see text]

scholarly journals Src tyrosine kinase is differentially expressed in the tumors of breast cancer patients treated with trastuzumab.

2020 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Breast Cancer ◽  
Tyrosine Kinase ◽  
Cancer Patients ◽  
Metastatic Breast ◽  
The United States ◽  
Differentially Expressed ◽  
Direct Result ◽  
Breast Cancer Patients ◽  
Src Tyrosine Kinase ◽  
Primary Tumors

Trastuzumab (Herceptin), a monoclonal antibody targeting the extracellular domain of the human epidermal growth factor receptor 2 (HER2) (1), is utilized for the treatment of adjuvant and metastatic breast cancer (2) in the United States and worldwide. We mined published microarray and gene expression data (3, 4) to discover in an unbiased fashion the most significant transcriptional changes associated with treatment with trastuzumab in patients with breast cancer. We identified the proto-oncogene and tyrosine kinase Src as among the genes most differentially expressed in the primary tumors of patients with breast cancer treated with trastuzumab. The primary tumors of breast cancer patients treated with trastuzumab expressed higher levels of Src messenger than did patients not treated with trastuzumab, and a single administration of trastuzumab was sufficient to result in differential expression of Src in primary tumors of the breast, demonstrating that a proto-oncogene (5) and gene whose product is necessary to drive MMTV-induced tumorigenesis of the mammary gland in mice6 is transcriptionally induced in primary tumors of the breast, likely as a direct result of treatment with trastuzumab.

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