Effect of general anesthetics on the tumor micro-environment in mouse models of breast cancers of spontaneous metastasis.

e15503 Background: Metastatic breast cancer is a pressing health concern worldwide. Various treatments have been developed but no significant long-term changes in overall survival are observed. Therefore, there is a demand to improve current therapies to treat this disease. Surgical resection of the primary tumors is essential in the treatment. However, accumulating evidence alludes to a role for volatile anesthetics which are used during the surgery in metastatic tumor development, but the mechanism remains largely unknown. We have shown anesthetics exert different effects on lung metastasis in mouse models of breast cancers. This study analyses the effect of general anesthetics in lung microenvironment associated with the increased metastases. Methods: Balb/c mice and NOD-SCID mice were orthotopically implanted with 4T1 cells and MDA-MB-231 cells respectively, in the mammary fat pad to generate primary tumors. Mice were subjected to the tested anesthetic during implantation and/or before and after surgery. Surgical dissection of primary tumor was performed under anesthesia with sevoflurane or an intravenous anesthetic propofol. Survival curve was constructed and analysed. Mice were euthanized to harvest tissues for histology and cell analysis. Results: As we previously reported, surgical dissection of primary tumor in mice under anesthesia with sevoflurane led to significantly more lung metastasis than with propofol in both syngeneic murine 4T1 and xenograft human MDA-MB-231 breast cancer models. Sevoflurane was associated with increased IL6(Li, Huang, & Lin, 2020). Here we show that anesthesia with sevoflurane resulted in changes of stroma composition in the lung, which was reversed by IL6 pathway interruption. Conclusions: Those results contribute to our understanding of effects of sevoflurane on cancer metastasis and suggest a potential therapeutic approach to overcome the risk of general anesthesia. Li, R., Huang, Y., & Lin, J. (2020). Distinct effects of general anesthetics on lung metastasis mediated by IL-6/JAK/STAT3 pathway in mouse models. Nat Commun, 11, 642.

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Host deficiency in ephrin-A1 inhibits breast cancer metastasis

F1000Research ◽

10.12688/f1000research.22689.1 ◽

2020 ◽

Vol 9 ◽

pp. 217 ◽

Cited By ~ 2

Author(s):

Eileen Shiuan ◽

Ashwin Inala ◽

Shan Wang ◽

Wenqiang Song ◽

Victoria Youngblood ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Growth ◽

Cancer Cell ◽

Lung Metastasis ◽

Primary Tumor ◽

Tumor Recurrence ◽

Cancer Metastasis ◽

Primary Tumor Growth ◽

Primary Tumors ◽

4T1 Cells

Background: The conventional dogma of treating cancer by focusing on the elimination of tumor cells has been recently refined to include consideration of the tumor microenvironment, which includes host stromal cells. Ephrin-A1, a cell surface protein involved in adhesion and migration, has been shown to be tumor suppressive in the context of the cancer cell. However, its role in the host has not been fully investigated. Here, we examine how ephrin-A1 host deficiency affects cancer growth and metastasis in a murine model of breast cancer. Methods: 4T1 cells were orthotopically implanted into the mammary fat pads or injected into the tail veins of ephrin-A1 wild-type (Efna1+/+), heterozygous (Efna1+/-), or knockout (Efna1-/-) mice. Tumor growth, lung metastasis, and tumor recurrence after surgical resection were measured. Flow cytometry and immunohistochemistry (IHC) were used to analyze various cell populations in primary tumors and tumor-bearing lungs. Results: While primary tumor growth did not differ between Efna1+/+, Efna1+/-, and Efna1-/- mice, lung metastasis and primary tumor recurrence were significantly decreased in knockout mice. Efna1-/- mice had reduced lung colonization of 4T1 cells compared to Efna1+/+ littermate controls as early as 24 hours after tail vein injection. Furthermore, established lung lesions in Efna1-/- mice had reduced proliferation compared to those in Efna1+/+ controls. Conclusions: Our studies demonstrate that host deficiency of ephrin-A1 does not impact primary tumor growth but does affect metastasis by providing a less favorable metastatic niche for cancer cell colonization and growth. Elucidating the mechanisms by which host ephrin-A1 impacts cancer relapse and metastasis may shed new light on novel therapeutic strategies.

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Evaluation of Sirt1 And Foxo’s In Primary Tumor And Distant Organ Metastasis Invaded By Benign And Highly Metastatic Breast Carcinoma Cells Under In Vitro And In Vivo Conditions.

10.21203/rs.3.rs-183690/v1 ◽

2021 ◽

Author(s):

Sayra Dilmac ◽

Nilay Kuscu ◽

Ayse Caner ◽

Sendegul Yildirim ◽

Burcak Yoldas ◽

...

Keyword(s):

Breast Cancer ◽

Primary Tumor ◽

Metastatic Breast ◽

Signal Pathways ◽

Breast Cancers ◽

Primary Tumors ◽

Metastatic Breast Carcinoma ◽

Liver Tissues

Abstract Breast cancer is the second most common cancer in women. In malignant breast cancers, tumor cells have the potential to metastasize to distant organs through the lymphatic system and blood circulation. The aim of this study is to evaluate the expression of SIRT1 and FoxO proteins in metastatic and nonmetastatic breast cancer cells and distant organs metastasis. In our study, SIRT1, p53, p21, and FoxO proteins have been evaluated in metastatic 4TLM and non-metastatic 67NR cell lines by immunocytochemistry in vitro and also in mice breast cancer model in vivo. Cells were orthotopically injected to mammary fat pads of 8-10 weeks old Balb/c female mice. Primary tumor, lung and liver tissues were removed and expressions of these proteins were evaluated by immunohistochemistry, western blot and RT-PCR. In addition, signal pathways that are related to SIRT and FoxO proteins were examined by using IPA core analysis. TCGA database was browsed for investigation of different genes.In primary tumors, SIRT1, p21, p53, E2F1 and FoxO expressions were higher in 67NR compared to 4TLM. In metastatic lung and liver tissues, the expression levels of SIRT1, FoxO1, FoxO3a and FoxO4 proteins were increased in 4TLM compared to 67NR. IPA and TCGA analysis have also revealed that SIRT1 and FoxO proteins are lower in primary tumors, but increased in metastatic stages. In conclusion, in primary tumors SIRT1 and FoxO expressions were decreased in 4TLM compared to 67NR. Moreover, SIRT1 and FoxO, especially expressed in metastatic cells. High level of FoxO expressions in metastatic stages in TNBC patients also supports its association with metastasis. Our findings suggest that SIRT1 and FoxO’s have crucial role in tumor progression metastatic process in breast cancer.

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Host deficiency in ephrin-A1 inhibits breast cancer metastasis

F1000Research ◽

10.12688/f1000research.22689.2 ◽

2020 ◽

Vol 9 ◽

pp. 217

Author(s):

Eileen Shiuan ◽

Ashwin Inala ◽

Shan Wang ◽

Wenqiang Song ◽

Victoria Youngblood ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Growth ◽

Cancer Cell ◽

Lung Metastasis ◽

Primary Tumor ◽

Tumor Recurrence ◽

Cancer Metastasis ◽

Primary Tumor Growth ◽

Primary Tumors ◽

4T1 Cells

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Detection of estrogen receptor in bone marrow from patients with metastatic breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.1987.5.11.1779 ◽

1987 ◽

Vol 5 (11) ◽

pp. 1779-1782 ◽

Cited By ~ 10

Author(s):

U Berger ◽

J L Mansi ◽

P Wilson ◽

R C Coombes

Keyword(s):

Breast Cancer ◽

Bone Marrow ◽

Endocrine Therapy ◽

Tumor Cells ◽

Epithelial Membrane Antigen ◽

Metastatic Breast ◽

Breast Cancers ◽

Double Staining ◽

Primary Tumors ◽

Er Positive

We devised a method of detecting estrogen receptors (ER) in bone marrow metastases from patients with breast cancer. The method involves a sequential double-staining immunocytochemical technique, with a monoclonal antibody to ER and a polyclonal antibody recognizing epithelial membrane antigen to confirm the epithelial nature of suspected tumor cells. Twenty-seven patients were assessed: ten were found to have ER-positive tumor cells in the bone marrow; ten had ER-negative cells; and the remaining seven patients had no tumor cells in the bone marrow smears. Of the ten patients with ER-positive cells, eight (80%) either had a response to endocrine therapy, implying that they possess ER-positive breast cancers, or had ER-positive primary tumors as determined by the dextran-coated charcoal biochemical assay (DCC). Of the ten patients with ER-negative cells in the bone marrow, eight failed to respond to endocrine therapy. This technique therefore provides a means of predicting which patients will respond to endocrine therapy, and is particularly important in those patients whose ER status is unknown.

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Concordance of Genomic Variants in Matched Primary Breast Cancer, Metastatic Tumor, and Circulating Tumor DNA: The MIRROR Study

JCO Precision Oncology ◽

10.1200/po.18.00263 ◽

2019 ◽

pp. 1-16 ◽

Cited By ~ 3

Author(s):

Fernando Moreno ◽

Javier Gayarre ◽

Sara López-Tarruella ◽

María del Monte-Millán ◽

Antonio C. Picornell ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Primary Tumor ◽

Metastatic Breast ◽

Metastatic Tumor ◽

Circulating Tumor Dna ◽

Primary Tumors ◽

Genomic Variants ◽

Ctdna Analysis ◽

Tumor Dna

PURPOSE Genetic heterogeneity between primary tumors and their metastatic lesions has been documented in several breast cancer studies. However, the selection of therapy for patients with metastatic breast cancer and the search for biomarkers for targeted therapy are often based on findings from the primary tumor, mainly because of the difficulty of distant metastasis core biopsies. New methods for monitoring genomic changes in metastatic breast cancer are needed (ie, circulating tumor DNA [ctDNA] genomic analysis). The objectives of this study were to assess the concordance of genomic variants between primary and metastatic tumor tissues and the sensitivity of plasma ctDNA analysis to identify variants detected in tumor biopsies. PATIENTS AND METHODS Next-generation sequencing technology was used to assess the genomic mutation profile of a panel of 54 cancer genes in matched samples of primary tumor, metastatic tumor, and plasma from 40 patients with metastatic breast cancer. RESULTS Using Ion Torrent technology (ThermoFisher Scientific, Waltham, MA), we identified 110 variants that were common to the primary and metastatic tumors. ctDNA analysis had a sensitivity of 0.972 in detecting variants present in both primary and metastatic tissues. In addition, we identified 13 variants in metastatic tissue and ctDNA not present in primary tumor. CONCLUSION We identified genomic variants present in metastatic biopsies and plasma ctDNA that were not present in the primary tumor. Deep sequencing of plasma ctDNA detected most DNA variants previously identified in matched primary and metastatic tissues. ctDNA might aid in therapy selection and in the search for biomarkers for drug development in metastatic breast cancer.

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Clinical and pathologic characteristics of patients with breast cancer and a second non-breast primary tumor.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e11539 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. e11539-e11539

Author(s):

Gul Atalay Basaran ◽

Aziz Yazar ◽

Cihan Uras ◽

Evrim Tezcanli ◽

Devrim Cabuk ◽

...

Keyword(s):

Breast Cancer ◽

Lung Cancer ◽

Primary Tumor ◽

Breast Tumor ◽

Cancer Metastasis ◽

Histological Grade ◽

Breast Tumors ◽

Second Primary ◽

Primary Tumors ◽

Second Primary Tumors

e11539 Background: We aimed to investigate the clinical and pathologic characteristics of patients with breast cancer (BC) who had a non-breast primary tumor and treated in our hospital. Methods: We identified BC patients with a second non-breast primary tumor retrospectively in our database. The tumors arising in a sequence by less than 2 months are accepted as synchronous malignancies. We noted clinical and pathological characteristics of breast tumors and analyzed the relapse patterns, the frequency and type of second non-breast primary tumors. Results: A total of 48 patients were identified. Median age was 59 years old. Thirty-four patients were postmenopausal, 41 tumors were IDC, 2 were DCIS only, eight were multiffocal. Two patients had metastatic BC at the time of diagnosis. Ninety-three (n: 26) % patients had breast conserving surgery, 2 had bilateral BC. Twenty-eight patients had node negative disease, 12 had node positive disease and 2 had micrometatatic nodal involvement. Fifty-four % were T1, 31% were T2 tumors. Histological grade was 3 for 14, 2 for 15 and 1 for 7 breast tumors. Forty patients had ER positive disease, 4 had ER/ PR negative disease, 2 tumors were triple negative and 6 tumors were Her-2 positive. Among non-breast second primary tumors; 29 arose after, 11 arose before the diagnosis of BC and 8 arose synchronously with BC. The most common non-breast second primary tumors were as follows: 15% lung cancer, 20% colorectal cancers, 13% ovarian cancer, 10% thyroid cancer, and 8% lymphoma/leukemia. With a median follow up of 76 months, there were 6 relapses; 4 of them were BC relapses. Among these 4 BC relapses, 3 patients had brain metastases and one patient had bone metastasis. There were 4 deaths; 2 were due to BC metastases, one was due to rectal cancer metastasis and the other was due to relapse of sarcoma. Conclusions: Most breast tumors were at early stage and were hormone sensitive. The most common second non-breast primary tumors arising after diagnosis of BC were colorectal, thyroid and lung cancers. The most common second non-breast tumor arising synchronously with BC was lung cancer and the most common second non-breast tumor arising before diagnosis of BC was lymphoma/leukemia.

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The effect of trastuzumab therapy on clinical benefit from fulvestrant treatment for metastatic estrogen receptor-positive breast cancer patients.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.26_suppl.155 ◽

2014 ◽

Vol 32 (26_suppl) ◽

pp. 155-155

Author(s):

Mahmoud Charif ◽

Elyse E. Lower ◽

Diane Kennedy ◽

Harriet Kumar ◽

Shugufta Khan ◽

...

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Metastatic Breast Cancer ◽

Clinical Benefit ◽

Primary Tumor ◽

Endocrine Resistance ◽

Metastatic Breast ◽

Primary Tumors ◽

Duration Of Therapy ◽

Her 2

155 Background: Overexpression of HER2/neu is associated with tamoxifen resistance in breast cancer (Osborne CK et al. J Natl Canc Inst 2003; 95:353-361). However pts may present with both estrogen receptor (ER) and HER2/neu + tumors. The benefit of adding fulvestrant to trastuzumab is unclear. The objective of the study was to determine the effect of trastuzumab on fulvestrant therapy. Methods: This was an IRB approved record review of patients (pts) from three medical oncologists with biopsy-proven ER+ metastatic breast cancer treated with fulvestrant who also had their primary tumor tested for HER2/neu. Demographic data collected included age at diagnosis, type and stage of cancer, original and metastatic ER, progesterone receptor (PR), and HER-2/neu biomarkers, and site(s) of metastasis, and primary local and systemic treatment. All pts with HER-2/neu + primary tumors received trastuzumab. The duration of fulvestrant therapy was calculated. Time to clinical disease progression on fulvestrant was measured as a surrogate for duration of clinical benefit. Results: Eighty-five metastatic ER+ fulvestrant treated breast cancer pts with known primary tumor HER2/neu status were identified and the duration of therapy calculated. All eleven (13%) pts with documented HER2/neu + primary tumors received trastuzumab. The duration of therapy for HER2/neu + pts (772 (51-1911) days (median (range)) was longer than HER2/neu negative pts (360 (60-2,739) days, p=0.059). The median duration of fulvestrant therapy was 425 days. Pts with HER2/neu + tumors were more likely to be treated beyond the median fulvestrant therapy with an odds ratio of 6.2 (1.26 to 30.92 95% confidence interval, p=0.0249). Conclusions: Trastuzumab plus fulvestrant therapy was associated with a more prolonged clinical response than fulvestrant alone in pts with metastatic breast cancer. This synergism may be due to the effect of trastuzumab inhibiting the activation of transcriptional coactivator MED1, a recently discovered key crosstalk point between HER2/neu and ER signaling pathways in mediating endocrine resistance (Cancer Res 2012;72(21):5625;PLoS One 2013; 8:e70641).

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The Metabolic Mechanisms of Breast Cancer Metastasis

Frontiers in Oncology ◽

10.3389/fonc.2020.602416 ◽

2021 ◽

Vol 10 ◽

Author(s):

Lingling Wang ◽

Shizhen Zhang ◽

Xiaochen Wang

Keyword(s):

Breast Cancer ◽

Cancer Metastasis ◽

Metastatic Breast ◽

Breast Cancer Metastasis ◽

Metabolic Reprogramming ◽

Breast Cancers ◽

Extrinsic Factors ◽

Intrinsic Factors ◽

Metastatic Sites

Breast cancer is one of the most common malignancy among women worldwide. Metastasis is mainly responsible for treatment failure and is the cause of most breast cancer deaths. The role of metabolism in the progression and metastasis of breast cancer is gradually being emphasized. However, the regulatory mechanisms that conduce to cancer metastasis by metabolic reprogramming in breast cancer have not been expounded. Breast cancer cells exhibit different metabolic phenotypes depending on their molecular subtypes and metastatic sites. Both intrinsic factors, such as MYC amplification, PIK3CA, and TP53 mutations, and extrinsic factors, such as hypoxia, oxidative stress, and acidosis, contribute to different metabolic reprogramming phenotypes in metastatic breast cancers. Understanding the metabolic mechanisms underlying breast cancer metastasis will provide important clues to develop novel therapeutic approaches for treatment of metastatic breast cancer.

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Biglycan (BGN) is differentially expressed in metastatic breast cancer, both in metastases to the brain and to the lymph nodes.

10.31219/osf.io/h93pf ◽

2020 ◽

Author(s):

Shahan Mamoor

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Primary Tumor ◽

Metastatic Breast ◽

Metastatic Tumor ◽

Clinical Problem ◽

Differentially Expressed ◽

Down Regulation ◽

Primary Tumors ◽

The Brain

Metastasis to the brain is a clinical problem in patients with breast cancer (1-3). We mined published microarray data (4, 5) to compare primary and metastatic tumor transcriptomes to discover genes associated with brain metastasis in patients with metastatic breast cancer. We found that biglycan, encoded by BGN, was among the genes whose expression was most different in the brain metastases of with patients with metastatic breast cancer as compared to primary tumors of the breast. Interestingly, biglycan was also among the genes most differentially expressed transcriptome-wide when comparing primary tumors of the breast to normal breast tissue. We observed significant down-regulation of biglycan in metastasis to the brain. Molecular functions and down-regulation of BGN may be important for metastasis of primary tumor-derived cancer cells the brain in humans with metastatic breast cancer, and suggests a role for changes in biglycan expression during a spectrum of transformation from benign tissue of the breast, primary tumor and finally to metastasis of the brain.

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Tomodensitometric aspects of Metastatic Breast Cancer seen in medical imaging in University Hospital Center Luxembourg

10.36811/ojrmi.2020.110007 ◽

2020 ◽

pp. 15-20

Author(s):

Camara MA ◽

Coulibaly S ◽

Mariko M ◽

Traore MM ◽

Ndiaye M ◽

...

Keyword(s):

Breast Cancer ◽

Medical Imaging ◽

Ct Scan ◽

Teaching Hospital ◽

Cancer Metastasis ◽

Metastatic Breast ◽

University Hospital ◽

Health Concern ◽

Important Place ◽

Secondary Lesion

Introduction: Breast cancer is the first cancer in woman worldwide. Its prognosis depends on early diagnosis and treatment. CT-scan has an important place in the diagnostic screening and the surveillance of this disease. The goal of this study was to assess the place of CT-scan in extension screening of breast cancer in the Department of Medical Imaging of the Teaching Hospital Mother-Child “Le Luxembourg”. Methods: It is a descriptive study on the retrospective compilation of CT-scan data of patients in the Department of Medical Imaging of the Teaching Hospital Mother-Child “Le Luxembourg” from May 1st to November 30th 2017. Were enrolled all patients, regardless of gender or age, with breast cancer histologically confirmed and who developed at least one secondary lesion found by CT-scan. CT-scan was performed before and after treatment. CT-scan machines were HITACHI® SUPRIA 16 bars and TOSHIBA® 04 bars, without and with Iodine 350mg intravenous injection. Results: Over seven months, 44 patients were enrolled with a mean age of 49 years and females were predominant. A family history of breast cancer was found in 13% of cases and invasive ductal carcinoma represented 95.54%. The main metastases were multi visceral (31.82%), pleural pulmonary (70.75%), ganglionic (63.63%), hepatic (27.27%) and bone (18.18%). Conclusion: Breast cancer is a public health concern with a clear predominance of women. In our context, CT-scan still has an important place in the research of secondary lesion in addition to the surveillance of this disease. Keywords: CT-scan Breast cancer; Metastasis; UHC Luxembourg

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