Differential MicroRNA Landscape Triggered by Estrogens in Cancer Associated Fibroblasts (CAFs) of Primary and Metastatic Breast Tumors

Cancer associated fibroblasts (CAFs) play a main role in breast cancer progression and metastasis. Estrogens modulate in breast CAFs the expression of microRNAs (miRNAs) that are involved in the development of many tumors. In order to provide novel insights on the regulation of miRNAs by estrogens in breast cancer, we analyzed the expression of 754 miRNAs in CAFs obtained from primary mammary tumors and CAFs derived from a cutaneous breast cancer metastasis. Using the TaqMan™ Human MicroRNA Array, we found that 17β-estradiol (E2) modulates numerous peculiar and common miRNAs in CAFs derived from primary and the metastatic malignancies. In particular, we assessed that E2 modulates 133 miRNAs (41 up and 92 downregulated) in CAFs derived from primary breast tumors, whereas E2 modulates 415 miRNAs (399 up and 16 downregulated) in CAFs derived from a cutaneous metastasis of breast carcinoma. Therefore, a number of miRNAs three times higher in metastatic CAFs with respect to primary breast CAFs was found modulated by E2. Our findings shed new light on the cumulative regulation of miRNAs by E2 in the main players of the tumor microenvironment as CAFs. Moreover, our data may be taken into consideration that is useful toward innovative prognostic and therapeutic approaches in breast cancer progression.

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The Role of CCL21/CCR7 Chemokine Axis in Breast Cancer Progression

Cancers ◽

10.3390/cancers12041036 ◽

2020 ◽

Vol 12 (4) ◽

pp. 1036 ◽

Cited By ~ 2

Author(s):

Balsam Rizeq ◽

Mohammed Imad Malki

Keyword(s):

Breast Cancer ◽

Cancer Progression ◽

Chemokine Receptor ◽

Chemokine Receptors ◽

Cancer Metastasis ◽

Cellular Proliferation ◽

Inflammatory Diseases ◽

Breast Cancer Metastasis ◽

Breast Cancer Progression ◽

Cellular Interactions

Breast cancer is a leading cause of cancer-related deaths worldwide, predominantly caused by metastasis. It is generally accepted that the pattern of breast cancer metastasis is largely determined by the interaction between the chemokine receptors on cancer cells and the chemokines expressed at the sites of metastatic disease. Chemokine receptors belong to the G-protein-coupled receptors (GPCRs) family that appear to be implicated in inflammatory diseases, tumor growth and metastasis. One of its members, C-C Chemokine receptor 7 (CCR7), binds chemokines CCL19 and CCL21, which are important for tissue homeostasis, immune surveillance and tumorigenesis. These receptors have been shown to induce the pathobiology of breast cancer due to their ability to induce cellular proliferation and migration upon the binding of the cognate chemokine receptors. The underlying signaling pathways and exact cellular interactions within this biological system are not fully understood and need further insights. Thus, in this review, we summarize the essential roles of CCR7 and its receptors in breast cancer progression. Furthermore, we discuss the mechanisms of regulation that may lead to novel opportunities for therapeutic intervention. Despite the enormous advances in our knowledge of the nature of the chemokines in breast cancer metastasis, research about the involvement of CCR7 in cancer progression is still limited. Therefore, further studies are essential to illustrate the distinct roles of CCR7 in cancer progression and validate its potential as a preventive bio-factor for human breast cancer metastasis by targeting chemokine receptor genes.

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Quercetin: Silent Retarder of Fatty Acid Oxidation in Breast Cancer Metastasis Through Steering of Mitochondrial CPT1

10.21203/rs.3.rs-849234/v1 ◽

2021 ◽

Author(s):

Bhuban Ruidas ◽

Tapas Kumar Sur ◽

Chitrangada Das Mukhopadhyay ◽

Koel Sinha ◽

Sutapa Som Chaudhury ◽

...

Keyword(s):

Breast Cancer ◽

Fatty Acid ◽

Fatty Acid Oxidation ◽

Cancer Progression ◽

Cancer Metastasis ◽

Metastatic Breast ◽

Cancer Therapeutics ◽

Breast Cancer Progression ◽

Acid Oxidation ◽

Mice Model

Abstract Recent evidence concreted that maximum energy in metastatic breast cancer progression is supplied by fatty acid oxidation (FAO) governed by a rate-limiting enzyme, carnitine palmitoyltransferase 1 (CPT1). Therefore, active limitation of FAO could be an emerging aspect to inhibit breast cancer progression. Herein, for the first time we have introduced Quercetin (QT) from a non-dietary source (Mikania micrantha Kunth) to seize the FAO in triple-negative breast cancer cells (TNBC) through an active targeting of CPT1. Apart from successive molecular quantification, QT has resulted a significant reduction in the intracellular mitochondrial respiration and glycolytic function limiting extensive ATP production. In turn, QT has elevated the reactive oxygen species (ROS) and depleted antioxidant level to induce anti-metastatic and cell apoptosis activities. Real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) investigated the FAO associated gene expression resulting significant depletion in FAO which were further confirmed through the successful in-silico molecular docking prediction for active binding potentiality of QT to CPT1. Subsequently, QT has shown an excellent in-vivo antitumor activities through the altered lipid profile and oxidative stress healing capabilities in female breast cancer BALB/c mice model. Therefore, all the obtained data significantly grounded the fact that QT could be a promising metabolism-targeted breast cancer therapeutics.

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A sense-antisense RNA interaction promotes breast cancer metastasis via regulation of NQO1 expression

10.1101/2021.10.08.463652 ◽

2021 ◽

Author(s):

Bruce Culbertson ◽

Kristle Garcia ◽

Daniel Markett ◽

Hosseinali Asgharian ◽

Li Chen ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Cancer Progression ◽

Antisense Rna ◽

Cancer Metastasis ◽

Metastatic Breast ◽

Breast Cancer Metastasis ◽

Breast Cancer Cell Lines ◽

Antisense Rnas ◽

Rna Interaction

Antisense RNAs are ubiquitous in human cells, yet the role that they play in healthy and diseased states remains largely unexplored. Here, we developed a computational framework to catalog and profile antisense RNAs and applied it to poorly and highly metastatic breast cancer cell lines. We identified one antisense RNA that plays a functional role in driving breast cancer progression by upregulating the redox enzyme NQO1, and hence named NQO1-antisense RNA or NQO1-AS. This upregulation occurs via a stabilizing interaction between NQO1-AS and its complementary region in the 3'UTR of NQO1 mRNA. By increasing expression of NQO1 protein, breast cancer cells are able to tolerate higher levels of oxidative stress, enabling them to colonize the lung. During this process the cancer cells become dependent on NQO1 to protect them from ferroptosis. We have shown that this dependence can be exploited therapeutically in xenograft models of metastasis. Together, our findings establish a previously unknown role for NQO1-AS in the progression of breast cancer by serving as a post-transcriptional regulator of RNA processing and decay for its sense mRNA.

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505. THE ROLE OF Adamts1 IN BREAST CANCER PROGRESSION AND METASTASIS

Reproduction Fertility and Development ◽

10.1071/srb09abs505 ◽

2009 ◽

Vol 21 (9) ◽

pp. 105

Author(s):

I. A. Tan ◽

K. M. Frewin ◽

C. Ricciardelli ◽

D. L. Russell

Keyword(s):

Breast Cancer ◽

Blood Vessel ◽

Cancer Progression ◽

Cancer Metastasis ◽

Breast Cancer Metastasis ◽

Breast Cancer Progression ◽

Vessel Density ◽

Blood Vessel Density ◽

Immunohistochemical Markers ◽

Significant Difference

The extracellular protease Adamts1 is a vital enzyme involved in normal development and has been associated with various processes of extracellular matrix (ECM) remodelling including ovulation and pathologies exhibiting disrupted ECM. In the PyMT-MMTV mouse mammary cancer model we have demonstrated reduced tumour growth and pulmonary metastasis incidence in Adamts1–/– mice. Furthermore, benign DCIS lesions of the mammary gland were significantly more common in Adamts1–/– mice. To better understand the mechanisms surrounding Adamts1 mediated progression from DCIS to invasive cancer we next investigated proliferation, apoptosis, blood vessel density and/or extracellular remodelling. Morphometric comparisons were performed using immunohistochemical markers of proliferation (Ki67) and apoptosis (active caspase3) as well as vasculature (CD34), and known Adamts1 proteolytic target, versican in wildtype and Adamts1-/-PyMT tumours. Our analysis revealed that no significant difference in proliferation between the two genotypes, but Adamts1–/– had increased apoptosis compared with Adamts1+/+ tumours. Contrary to previous reports suggesting Adamts1 is antiangiogenic, no significant difference was found in blood vessel density between Adamts1–/– compared with Adamts1+/+ tumours. Interestingly, versican abundance in peritumoural stroma was lower in Adamts1–/– tumours. This latter finding may provide an explanation for the reduced metastasis incidence found after Adamts1gene inactivation, as many previous studies have associated peritumoral versican abundance to metastasic progression. Our findings increase the understanding of mechanisms whereby Adamts1 promotes breast cancer metastasis by showing its role in increasing cell survival, as well as modulating the stromal ECM environment through which it may promote invasion and metastasis. The involvement of Adamts1 in breast cancer progression presents this protease as a potential novel target for reducing metastasis incidence.

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Metastasis: A Bane of Breast Cancer Therapy

European Medical Journal ◽

10.33590/emj/20-00039 ◽

2020 ◽

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Cancer Progression ◽

Cancer Metastasis ◽

Epithelial Mesenchymal Transition ◽

Tumour Size ◽

Metastatic Breast ◽

Metastatic Potential ◽

Breast Cancer Metastasis ◽

Mesenchymal Transition

The underlying mechanisms of metastasis in patients with breast cancer is still poorly understood. Approximately 6% of patients with breast cancer present with metastasis at the time of diagnosis. Metastatic breast cancer is difficult to treat and patients with breast cancer with distant metastasis have a significantly lower 5-year survival rate compared to patients with localised breast cancer (27% and 99%, respectively). During breast cancer progression, tumour cells first metastasise to nearby draining lymph nodes and then to distant organs, primarily bone, lungs, liver, and brain. In this brief review, the authors discuss breast cancer metastasis, the role of epithelial–mesenchymal transition and the contributions of the immune system to the metastatic process. The authors also briefly discuss whether there is any relationship between tumour size and metastatic potential, and recent advances in treatment for metastatic breast cancer. The studies highlighted suggest that immunotherapy may play a more significant role in future patient care for metastatic breast cancer.

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A sense-antisense RNA interaction promotes breast cancer metastasis via regulation of NQO1 expression

10.21203/rs.3.rs-967511/v1 ◽

2021 ◽

Author(s):

Bruce Culbertson ◽

Kristle Garcia ◽

Daniel Markett ◽

Hosseinali Asgharian ◽

Li Chen ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Cancer Progression ◽

Antisense Rna ◽

Cancer Metastasis ◽

Metastatic Breast ◽

Breast Cancer Metastasis ◽

Breast Cancer Cell Lines ◽

Antisense Rnas ◽

Rna Interaction

Abstract Antisense RNAs are ubiquitous in human cells, yet the role that they play in healthy and diseased states remains largely unexplored. Here, we developed a computational framework to catalog and profile antisense RNAs and applied it to poorly and highly metastatic breast cancer cell lines. We identified one antisense RNA that plays a functional role in driving breast cancer progression by upregulating the redox enzyme NQO1, and hence named NQO1-antisense RNA or NQO1-AS. This upregulation occurs via a stabilizing interaction between NQO1-AS and its complementary region in the 3’UTR of NQO1 mRNA. By increasing expression of NQO1 protein, breast cancer cells are able to tolerate higher levels of oxidative stress, enabling them to colonize the lung. During this process the cancer cells become dependent on NQO1 to protect them from ferroptosis. We have shown that this dependence can be exploited therapeutically in xenograft models of metastasis. Together, our findings establish a previously unknown role for NQO1-AS in the progression of breast cancer by serving as a post-transcriptional regulator of RNA processing and decay for its sense mRNA.

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Cooperation of Cancer Stem Cell Properties and Epithelial-Mesenchymal Transition in the Establishment of Breast Cancer Metastasis

Journal of Oncology ◽

10.1155/2011/591427 ◽

2011 ◽

Vol 2011 ◽

pp. 1-7 ◽

Cited By ~ 30

Author(s):

Tetsu Hayashida ◽

Hiromitsu Jinno ◽

Yuko Kitagawa ◽

Masaki Kitajima

Keyword(s):

Breast Cancer ◽

Stem Cell ◽

Cancer Stem Cell ◽

Cancer Progression ◽

Cancer Metastasis ◽

Epithelial Mesenchymal Transition ◽

Metastatic Tumor ◽

Breast Cancer Metastasis ◽

Cell Junctions ◽

Mesenchymal Transition

Epithelial-mesenchymal transition (EMT) is a multistep process in which cells acquire molecular alterations such as loss of cell-cell junctions and restructuring of the cytoskeleton. There is an increasing understanding that this process may promote breast cancer progression through promotion of invasive and metastatic tumor growth. Recent observations imply that there may be a cross-talk between EMT and cancer stem cell properties, leading to enhanced tumorigenicity and the capacity to generate heterogeneous tumor cell populations. Here, we review the experimental and clinical evidence for the involvement of EMT in cancer stem cell theory, focusing on the common characteristics of this phenomenon.

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Facial nerve palsy as the first sign of late breast cancer metastasis to the temporal bone

Vojnosanitetski pregled ◽

10.2298/vsp210212040d ◽

2021 ◽

pp. 40-40

Author(s):

Zoran Dudvarski ◽

Nenad Arsovic ◽

Milovan Dimitrijevic ◽

Sasa Jakovljevic ◽

Novica Boricic ◽

...

Keyword(s):

Breast Cancer ◽

Hearing Loss ◽

Facial Nerve ◽

Temporal Bone ◽

Cancer Metastasis ◽

Metastatic Breast ◽

Breast Cancer Metastasis ◽

Facial Nerve Paralysis ◽

Nerve Paralysis ◽

Radiological Diagnostics

Introduction. Late metastases of malignant tumors in the temporal bone are very rare lesions. They can be asymptomatic for a long time, and usually manifest themselves in the form of hearing loss, dizziness, tinnitus, and paralysis of the facial nerve. Modern radiological diagnostics and explorative surgery with biopsy are essential for diagnosis. Case report. We present a rare and unusual case of a 66-year-old female patient with a facial nerve paralysis that appeared as the first sign of metastatic breast cancer in the temporal bone 10 years after treatment. A sudden hearing loss and dizziness occurred six months later and value of CA 15-3 was elevated. Scintigraphy pointed to susceptible metastatic deposits of the axial skeleton, without lesions in the temporal bone. Finally, repeated computerized tomography revealed osteolytic changes of the temporal bone six months after that. Immunohistochemical analysis of mastoid tissue samples confirmed that it was a breast cancer metastasis. One year after palliative radiotherapy and oral hormone therapy, a patient has a good general condition with better function of the facial nerve. Conclusion. A high degree of clinical suspicion sometimes requires repeated radiological diagnostics in order to detect osteolytic metastatic changes in the temporal bone, but also in other bone structures within the hematogenous dissemination of the malignant disease.

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A Model of Dormant-Emergent Metastatic Breast Cancer Progression Enabling Exploration of Biomarker Signatures

Molecular & Cellular Proteomics ◽

10.1074/mcp.ra117.000370 ◽

2018 ◽

Vol 17 (4) ◽

pp. 619-630 ◽

Cited By ~ 20

Author(s):

Amanda M. Clark ◽

Manu P. Kumar ◽

Sarah E. Wheeler ◽

Carissa L. Young ◽

Raman Venkataramanan ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Cancer Progression ◽

Metastatic Breast ◽

Breast Cancer Progression

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Serum ANGPTL2 Levels Reflect Clinical Features of Breast Cancer Patients: Implications for the Pathogenesis of Breast Cancer Metastasis

The International Journal of Biological Markers ◽

10.5301/jbm.5000080 ◽

2014 ◽

Vol 29 (3) ◽

pp. 239-245 ◽

Cited By ~ 22

Author(s):

Motoyoshi Endo ◽

Yutaka Yamamoto ◽

Masahiro Nakano ◽

Tetsuro Masuda ◽

Haruki Odagiri ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Clinical Features ◽

Cancer Progression ◽

Breast Cancer Cells ◽

Cancer Metastasis ◽

Ductal Carcinoma ◽

Breast Cancer Metastasis ◽

Breast Cancer Patients

Introduction Breast cancer is a leading cause of cancer-related death in women worldwide, and its metastasis is a major cause of disease mortality. Therefore, identification of the mechanisms underlying breast cancer metastasis is crucial for the development of therapeutic and diagnostic strategies. Our recent study of immunodeficient female mice transplanted with MDA-MB231 breast cancer cells demonstrated that tumor cell-derived angiopoietin-like protein 2 (ANGPTL2) accelerates metastasis through both increasing tumor cell migration in an autocrine/paracrine manner, and enhancing tumor angiogenesis. To determine whether ANGPTL2 contributes to its clinical pathogenesis, we asked whether serum ANGPTL2 levels reflect the clinical features of breast cancer progression. Methods We monitored the levels of secreted ANGPTL2 in supernatants of cultured proliferating MDA-MB231 cells. We also determined whether the circulating ANGPTL2 levels were positively correlated with cancer progression in an in vivo breast cancer xenograft model using MDA-MB231 cells. Finally, we investigated whether serum ANGPTL2 levels were associated with clinical features in breast cancer patients. Results Both in vitro and in vivo experiments showed that the levels of ANGPTL2 secreted from breast cancer cells increased with cell proliferation and cancer progression. Serum ANGPTL2 levels in patients with metastatic breast cancer were significantly higher than those in healthy subjects or in patients with ductal carcinoma in situ or non-metastatic invasive ductal carcinoma. Serum ANGPTL2 levels in patients negative for estrogen receptors and progesterone receptors, particularly triple-negative cases, reflected histological grades. Conclusions These findings suggest that serum ANGPTL2 levels in breast cancer patients could represent a potential marker of breast cancer metastasis.

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