scholarly journals Human ribonuclease 1 serves as a secretory ligand of ephrin A4 receptor and induces breast tumor initiation

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Heng-Huan Lee ◽  
Ying-Nai Wang ◽  
Wen-Hao Yang ◽  
Weiya Xia ◽  
Yongkun Wei ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Tumor ◽  
Cell Communication ◽  
Tissue Microarrays ◽  
Stem Cell Marker ◽  
Tyrosine Kinase Receptor ◽  
Tumor Initiation ◽  
Breast Cancer Patients ◽  
Extracellular Rna ◽  
Breast Tumor Tissue

AbstractHuman ribonuclease 1 (hRNase 1) is critical to extracellular RNA clearance and innate immunity to achieve homeostasis and host defense; however, whether it plays a role in cancer remains elusive. Here, we demonstrate that hRNase 1, independently of its ribonucleolytic activity, enriches the stem-like cell population and enhances the tumor-initiating ability of breast cancer cells. Specifically, secretory hRNase 1 binds to and activates the tyrosine kinase receptor ephrin A4 (EphA4) signaling to promote breast tumor initiation in an autocrine/paracrine manner, which is distinct from the classical EphA4-ephrin juxtacrine signaling through contact-dependent cell-cell communication. In addition, analysis of human breast tumor tissue microarrays reveals a positive correlation between hRNase 1, EphA4 activation, and stem cell marker CD133. Notably, high hRNase 1 level in plasma samples is positively associated with EphA4 activation in tumor tissues from breast cancer patients, highlighting the pathological relevance of the hRNase 1-EphA4 axis in breast cancer. The discovery of hRNase 1 as a secretory ligand of EphA4 that enhances breast cancer stemness suggests a potential treatment strategy by inactivating the hRNase 1-EphA4 axis.

scholarly journals Investigating New Therapeutic Strategies Targeting Hyperinsulinemia's Mitogenic Effects in a Female Mouse Breast Cancer Model

Endocrinology ◽  
2013 ◽  
Vol 154 (5) ◽  
pp. 1701-1710 ◽  
Author(s):  
Ran Rostoker ◽  
Keren Bitton-Worms ◽  
Avishay Caspi ◽  
Zila Shen-Orr ◽  
Derek LeRoith
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Breast Tumor ◽  
Experimental Studies ◽  
Tumor Development ◽  
Treated Group ◽  
Tumor Growth Rate ◽  
Breast Cancer Patients ◽  
Mitogenic Effect

Abstract Epidemiological and experimental studies have identified hyperinsulinemia as an important risk factor for breast cancer induction and for the poor prognosis in breast cancer patients with obesity and type 2 diabetes. Recently it was demonstrated that both the insulin receptor (IR) and the IGF-IR mediate hyperinsulinemia's mitogenic effect in several breast cancer models. Although IGF-IR has been intensively investigated, and anti-IGF-IR therapies are now in advanced clinical trials, the role of the IR in mediating hyperinsulinemia's mitogenic effect remains to be clarified. Here we aimed to explore the potential of IR inhibition compared to dual IR/IGF-IR blockade on breast tumor growth. To initiate breast tumors, we inoculated the mammary carcinoma Mvt-1 cell line into the inguinal mammary fat pad of the hyperinsulinemic MKR female mice, and to study the role of IR, we treated the mice bearing tumors with the recently reported high-affinity IR antagonist-S961, in addition to the well-documented IGF-IR inhibitor picropodophyllin (PPP). Although reducing IR activation, with resultant severe hyperglycemia and hyperinsulinemia, S961-treated mice had significantly larger tumors compared to the vehicle-treated group. This effect maybe secondary to the severe hyperinsulinemia mediated via the IGF-1 receptor. In contrast, PPP by partially inhibiting both IR and IGF-IR activity reduced tumor growth rate with only mild metabolic consequences. We conclude that targeting (even partially) both IR and IGF-IRs impairs hyperinsulinemia's effects in breast tumor development while simultaneously sparing the metabolic abnormalities observed when targeting IR alone with virtual complete inhibition.

scholarly journals Cytomegalovirus, Macrophages and Breast Cancer

2017 ◽  
Vol 11 (1) ◽  
pp. 15-27 ◽  
Author(s):  
S. Pasquereau ◽  
F. Al Moussawi ◽  
W. Karam ◽  
M. Diab Assaf ◽  
A. Kumar ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Epithelial Cells ◽  
Human Cytomegalovirus ◽  
Breast Tumor ◽  
Poor Prognosis ◽  
Tumor Tissue ◽  
Tumor Associated Macrophages ◽  
Potential Implication ◽  
Breast Tumor Tissue

The human cytomegalovirus (HCMV) is a betaherpesvirus that is highly host specific, infects among others epithelial cells and macrophages, and has been recently mentioned as having oncomodulatory properties. HCMV is detected in the breast tumor tissue where macrophages, especially tumor associated macrophages, are associated with a poor prognosis. In this review, we will discuss the potential implication of HCMV in breast cancer with emphasis on the role played by macrophages.

Micropallet Technology for Investigating Tumor Cellular Profiles and Analysis of Rare Cell Subsets

2008 ◽  
Author(s):  
Nicholas M. Gunn ◽  
Mark Bachman ◽  
Edward L. Nelson ◽  
G.-P. Li
Keyword(s):  
Breast Cancer ◽  
United States ◽  
Cancer Patients ◽  
Invasive Breast Cancer ◽  
Breast Tumor ◽  
The United States ◽  
Therapeutic Strategies ◽  
Cellular Heterogeneity ◽  
Breast Cancer Patients ◽  
Critical Limits

Rationally designed, individualized therapeutic strategies have long been a desired objective for breast cancer patients and clinicians as an estimated 178,480 new cases of invasive breast cancer will be diagnosed among women in the United States this year and over 40,000 women are expected to die from the disease. [1] The increasing appreciation of breast tumor cellular heterogeneity raises fundamental questions as to the relative contributions of cellular subsets to the biologic behavior of an individual patient’s tumor. [2] As such, it has become increasingly clear that in many cases, an individualized strategy for the treatment of breast cancer would be of great benefit, and that the ability to isolate relevant cellular subsets from the main tumor population is one of the critical limits to accomplishing this goal.

scholarly journals Expression of MTDH and IL-10 Is an Independent Predictor of Worse Prognosis in ER-Negative or PR-Negative Breast Cancer Patients

2020 ◽  
Vol 9 (10) ◽  
pp. 3153
Author(s):  
Pei-Yi Chu ◽  
Shin-Mae Wang ◽  
Po-Ming Chen ◽  
Feng-Yao Tang ◽  
En-Pei Isabel Chiang
Keyword(s):  
Breast Cancer ◽  
Protein Expression ◽  
Mrna Expression ◽  
Cancer Patients ◽  
Expression Patterns ◽  
Hypoxia Inducible Factor ◽  
Tumor Hypoxia ◽  
Tissue Microarrays ◽  
Breast Cancer Patients ◽  
Worse Prognosis

(1) Background: Tumor hypoxia leads to metastasis and certain immune responses, and interferes with normal biological functions. It also affects glucose intake, down-regulates oxidative phosphorylation, and inhibits fatty-acid desaturation regulated by hypoxia-inducible factor 1α (HIF-1α). Although tumor hypoxia has been found to promote tumor metastasis, the roles of HIF-1α-regulated genes and their application are not completely integrated in clinical practice. (2) Methods: We examined the correlation between HIF-1α, metadherin (MTDH), and interleukin (IL)-10 mRNA expression, as well as their expression patterns in the prognosis of breast cancer using the Gene Expression Profiling Interactive Analysis (GEPIA) databases via a web interface; tissue microarrays (TMAs) were stained for MTDH and IL-10 protein expression using immunohistochemistry. (3) Results: HIF-1α, MTDH, and IL-10 mRNA expression are highly correlated and strongly associated with poor prognosis. MTDH and IL-10 protein expression of breast cancer patients usually harbored negative estrogen receptor (ER) or progesterone receptor (PR) status, and late-stage tumors have higher IL-10 expression. With regard to MTDH and IL-10 protein expression status for using univariate and multivariate analysis, the results showed that the protein expression of MTDH and IL-10 in ER-negative or PR-negative breast cancer patients have the worse prognosis. (4) Conclusions: we propose a new insight into hypoxia tumors in the metabolism and immune evidence for breast cancer therapy.

Can primary tumor markers of cancer-initiating cells predict lymph node positivity in breast cancer patients?

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 1121-1121
Author(s):  
Anees B. Chagpar ◽  
Veronique Neumeister ◽  
Donald R. Lannin ◽  
David Rimm
Keyword(s):  
Breast Cancer ◽  
Lymph Node ◽  
Cancer Patients ◽  
Tumor Markers ◽  
Tumor Size ◽  
Primary Tumor ◽  
Poor Prognosis ◽  
Tissue Microarrays ◽  
Median Number ◽  
Breast Cancer Patients

1121 Background: Cancer initiating cells, characterized by ALDH1 positivity and/or colocalization of ALDH1 and CD44, have been shown to be associated with poor prognosis in breast cancer patients. The prognostic value of these tumor markers with respect to prediction of lymph node (LN) status remains unclear. Methods: Tissue microarrays from a cohort of 223 breast cancer patients diagnosed between 2003 and 2007 were evaluated using the AQUA method for quantitative immunofluorescence for CD44 and ALDH1. These data, along with other clinicopathologic data, were correlated with LN positivity. Results: The median patient age of the cohort was 56 (range; 26-89), with a median tumor size of 1.5 cm. 72 (32.0%) patients were LN positive. The median number of LNs excised was 3 (range; 1-27). Of the LN positive patients, the median number of positive LNs was 1.5 (range; 1-24). Levels of CD44, ALDH1, and ALDH1 colocalizing with CD44 did not correlate with number of positive LNs (Spearman rho coefficients: -0.042, 0.131, and 0.058, respectively), nor overall LN status. Tumor size and lymphovascular invasion (LVI) were the only factors found to be significantly correlated with LN status. Conclusions: While ALDH1 colocalized with CD44 has been found to be associated with poor prognosis in breast cancer patients, these markers do not predict LN status. Given that the only factors that reliably predict LN status are tumor size and LVI, further work is required to find primary tumor markers that may predict LN status in order to spare patients axillary surgery. [Table: see text]

Effect of mast cells on efficacy of anti-angiogenic therapy by secreting matrix-degrading granzyme b.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 11522-11522
Author(s):  
Mark Wroblewski ◽  
Janna-Lisa Velthaus ◽  
Raimund Bauer ◽  
Volkmar Müller ◽  
Christian Schem ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Granzyme B ◽  
Resistance Mechanism ◽  
Disease Free Survival ◽  
Tissue Microarrays ◽  
Breast Cancer Patients ◽  
Free Survival ◽  
Angiogenic Therapy ◽  
Kaplan Meier

11522 Background: Resistance towards anti-angiogenic therapy (AAT) still represents a substantial clinical challenge. As mast cell (MC) density is known to correlate with tumor angiogenesis, we analyzed if inhibition of MC holds potential to increase efficacy of AAT in mice and cancer patients. Methods: C57BL/6J (WT), NSG or MC-deficient KitW-sh(Wsh) mice were subcutaneously injected with Panc02, EL4 or BxPC3 cells with or without bone marrow-derived MC. Tumors were treated with 20 mg/kg of anti-VEGFR2 antibodies (DC101) or 25 mg/kg cromoglicic acid. Tissue microarrays from n = 299 breast cancer patients from the GeparQuinto Phase 3 clinical trial were stained for MC and MC numbers were correlated with clinical data. Results: We observed that absence of MC reduced tumor growth and increased the efficacy of AAT in different tumor models. Intriguingly, AAT only initially reduced microvessel proliferation but this was abrogated over time as a result of MC-mediated resistance. We show that MC secrete increased amounts of granzyme b upon therapy, which mobilizes alternative pro-angiogenic factors from the tumor matrix. These factors act beside the targeted VEGFA-VEGFR2-axis and reinduce angiogenesis despite the presence of AAT. Importantly, MC-mediated resistance could be overcome using the FDA-approved MC inhibitor cromoglicic acid. In line with our preclinical data, high intratumoral MC density correlated with disease progression in HR+ breast cancer patients when Bevacizumab was added to standard neodjuvant chemotherapy (HR 8.45, p = 0.006). Accordingly, Kaplan-Meier curves indicated that disease free survival of patients with high tumoral MC density was numerically shorter in the whole cohort and significantly shorter in the HR+ cohort upon addition of AAT to chemotherapy (p = 0.168 and p = 0.004, respectively). Conclusions: Here we unravel a novel resistance mechanism, by which MC hamper efficacy of AAT in mice and cancer patients. In preclinical models this effect could be overcome by combining AAT with an FDA-approved MC inhibitor indicating high clinical relevance. Thus, combination of FDA-approved MC inhibitors with AAT might be a suitable approach to increase efficacy of AAT in the clinic.

Risk stratification in earl- stage luminal breast cancer patients treated with and without RT.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 568-568 ◽  
Author(s):  
Charlotta Wadsten ◽  
Pat W. Whitworth ◽  
Rakesh Patel ◽  
Jess Savala ◽  
Fredrik Warnberg ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Proportional Hazards ◽  
Risk Groups ◽  
Tissue Microarrays ◽  
Cox Proportional Hazards ◽  
Luminal Breast Cancer ◽  
Breast Cancer Patients ◽  
Luminal A ◽  
Kaplan Meier ◽  
Stage 1

568 Background: The goal was to develop and validate a biologic signature for 10-year ipsilateral invasive breast event (IBE) risk in luminal Stage 1 breast cancer (BC) patients treated surgically and either with or without radiation therapy (RT). Methods: This cohort was from Uppsala University and Västerås Hospitals diagnosed with Stage 1 BC and treated surgically between 1987 and 2004. Treatment was neither randomized nor strictly rules based, including adjuvant RT, Hormone Therapy (HT), and Chemotherapy (CT). Biomarkers (HER2, PR, Ki67, COX2, p16/INK4A, FOXA1 and SIAH2) were assessed on tissue microarrays in PreludeDx’s CLIA lab by board-certified pathologists. Risk groups were calculated using biomarkers and clinical factors age and size. A multivariate Cox proportional hazards analysis was used to determine hazard ratio for biologic signature. 10-year IBE risk was assessed using Kaplan-Meier survival analysis. Results: There were 423 luminal cases with biomarker data having 54 IBEs, and a median follow-up of 11.8 years. There were 372 patients treated with BCS and 51 with Mastectomy, and 325 received RT, 169 received HT, and 47 received CT. In a multivariate analysis, the biologic signature (HR = 1.6, p = 0.019) and RT (HR = 0.51, p = 0.027) were associated with IBE risk adjusting for other treatments (HT and CT) and Luminal A status (p = 0.37). For patients over 50 yrs of age with luminal A disease and treated without CT (n = 205), an elevated biologic signature identified a subset of patients with a 15% (+/- 14%) 10-year IBE risk without RT (n = 38) compared to a 4% (+/-6%) IBE risk with RT (n = 72), while patients with a low biologic signature had a 10-year IBE risk of 4% (+/- 4%) without RT (n = 26) and 3% (+/-5%) IBE risk with RT (n = 69). Conclusions: With further prospective validation, the biologic signature identified herein may provide a tool enabling improved management for women diagnosed with early luminal BC.

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