Association Between Ligands and Receptors Related to the Progression of Early Breast Cancer in Tumor Epithelial and Stromal Cells

Labovsky, Vivian; Martinez, Leandro Marcelo; Davies, Kevin; García‐Rivello, Hernán; Calcagno, María de Luján; Matas, Ayelén; Vallone, Valeria Beatriz Fernández; Wernicke, Alejandra; Choi, Hosoon; Chasseing, Norma Alejandra

doi:10.1016/j.clbc.2014.05.006

Cited by 17 publications

(21 citation statements)

References 38 publications

(52 reference statements)

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“…The MSCs are known to increase tumor progression, which is mediated by different cytokines such as OPG, TRAIL, IL-6, IL-8, CCL-5, CCL-2, and RANKL. These factors are known to increase the breast cancer development by regulating patient survival, bypassing apoptosis, invasion, migration and tumor angiogenesis [24]. OPG, TRAIL, and RANKL are significantly higher in tumor epithelial cells from patients with breast cancer than in epithelial cells of non-neoplastic breast tissues [25].…”

Section: Opg and Breast Cancermentioning

confidence: 99%

Osteoprotegerin rich tumor microenvironment: implications in breast cancer

Goswami

Sharma-Walia

2016

Oncotarget

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Osteoprotegerin (OPG) is a soluble decoy receptor for tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL). It belongs to the tumor necrosis factor receptor superfamily (TNFRSF). OPG was initially discovered to contribute to homeostasis of bone turnover due to its capability of binding to receptor activator of nuclear factor-kappaB (NF-kB). However, apart from bone turnover, OPG plays important and diverse role(s) in many biological functions. Besides having anti-osteoclastic activity, OPG is thought to exert a protective anti-apoptotic action in OPG-expressing tumors by overcoming the physiologic mechanism of tumor surveillance exerted by TRAIL. Along with inhibiting TRAIL induced apoptosis, it can induce proliferation by binding to various cell surface receptors and thus turning on the canonical cell survival and proliferative pathways. OPG also induces angiogenesis, one of the hallmarks of cancer, thus facilitating tumor growth. Recently, the understanding of OPG and its different roles has been augmented substantially. This review is aimed at providing a very informative overview as to how OPG affects cancer progression especially breast cancer.

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Section: Opg and Breast Cancermentioning

confidence: 99%

Osteoprotegerin rich tumor microenvironment: implications in breast cancer

Goswami

Sharma-Walia

2016

Oncotarget

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“…These tissues were processed and immunohistochemistry was used to determine the levels of ligands and receptors in TEpC and in spindle-shaped stromal cells, not associated with the vasculature, and it was completed as described in a previously work [15]. …”

Section: Methodsmentioning

confidence: 99%

“…Each sample was assayed in duplicate and was initially examined at 100× magnification followed by observation of five representative fields at 400× magnification along a projected Z-line. Expression levels were evaluated separately for the TEpCs and spindle-shaped stromal cells, not associated to the vasculature, per the percentage of positive cells and staining intensity, which were estimated according to the Allred score [15, 16]. The percentages of positive cells were assigned scores as follows: 0 (<10%), 1 (10%–30%), 2 (31%–60%), 3 (61%–90%), and 4 (>90%).…”

Section: Methodsmentioning

confidence: 99%

“…The percentages of positive cells were assigned scores as follows: 0 (<10%), 1 (10%–30%), 2 (31%–60%), 3 (61%–90%), and 4 (>90%). Staining intensity was scored as 0 (no staining), 1 (weak), 2 (moderate), and 3 (strong), according to the relative intensity of staining of TEpCs analyzed using the anti-cytokeratin antibody [15, 18]. The final staining score was calculated using the sum of the percentage of positive cells and the staining intensity score, which ranged from 0 to 7.…”

Section: Methodsmentioning

confidence: 99%

“…The interaction of malignant and non-malignant cells influences tumorigenesis, tumor growth, metastasis, and response to therapy [6–15]. Our group demonstrated that spindle-shaped stromal cells are not associated with the vasculature and TEpCs from primary invasive ductal breast cancer in women with stage I or II express molecules such as osteoprotegerin ( OPG), tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), receptor activator of nuclear factor kappa B ligand ( RANKL), stromal cell derived factor ( SDF)-1, interleukin (IL)-6, chemokine (C-C motif) ligand-2 (CCL-2) and their receptors [15]. These molecules, which are likely involved in the interactions between these cell types, mediate proliferation, survival, migration, and intravasation of TEpCs as well as angiogenesis in the primary tumor [15].…”

Section: Introductionmentioning

confidence: 99%

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Prognostic significance of TRAIL-R3 and CCR-2 expression in tumor epithelial cells of patients with early breast cancer

et al. 2017

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BackgroundTumor epithelial cells (TEpCs) and spindle-shaped stromal cells, not associated with the vasculature, of patients with early breast cancer express osteoprotegerin (OPG), tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), receptor activator of nuclear factor kappa B ligand, stromal cell derived factor-1, interleukin-6, macrophage colony stimulating factor, chemokine (C-C motif) ligand-2 (CCL-2) and their receptors at significantly higher levels compared with non-neoplastic breast tissues. We evaluated the clinicopathological significance of these ligands and receptors in TEpC and spindle-shaped stromal cells, not associated with the vasculature, to determine their impact on prognosis of patients with early-stage breast cancer.MethodsWe conducted immunohistochemical analyses of protein expression in primary tumors of patients with early breast cancer and analyzed their association with standard prognostic parameters and clinical outcomes, including local relapse, metastatic recurrence, disease-free survival (DFS), metastasis-free survival (MFS), and overall survival (OS).ResultsElevated levels of TRAIL-R3 and chemokine (C-C motif) receptor 2 (CCR-2) in TEpCs and OPG and CCL-2 in stromal cells were significantly associated with a higher risk of metastasis (p = 0.032, p = 0.003, p = 0.038, and p = 0.049; respectively). Moreover, high expression of TRAIL-R3 and CCR-2 in TEpCs was associated with shorter DFS, MFS, and OS. High TRAIL-R3 expression in TEpCs was an independent prognostic factor for DFS and OS, and high CCR-2 expression in these cells was an independent prognostic factor for MFS.ConclusionsHigh levels of TRAIL-R3 and CCR-2 expression in TEpCs identified patients with early breast cancer with poor outcomes.

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Elevated MMP9 expression in breast cancer is a predictor of shorter patient survival

Joseph

Alsaleem

Orah

et al. 2020

Breast Cancer Res Treat

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Purpose MMP9 is a matricellular protein associated with extracellular matrix (ECM) remodelling, that promotes tumour progression, and modulates the activity of cell adhesion molecules and cytokines. This study aims to assess the prognostic value of MMP9 and its association with cytoskeletal modulators in early-stage invasive breast cancer (BC). Methods MMP9 expression was evaluated by immunohistochemistry using a well-characterised series of primary BC patients with long-term clinical follow-up. Association with clinicopathological factors, patient outcome and ECM remodelling BC-biomarkers were investigated. METABRIC dataset, BC-GenExMiner v4.0 and TCGA were used for the external validation of MMP9 expression. GSEA gene enrichment analyses were used to evaluate MMP9 associated pathways. Results MMP9 immunopositivity was observed in the stroma and cytoplasm of BC cells. Elevated MMP9 protein levels were associated with high tumour grade, high Nottingham Prognostic Index, and hormonal receptor negativity. Elevated MMP9 protein expression correlated significantly with cytokeratin 17 (Ck17), Epidermal Growth Factor Receptor (EGFR), proliferation (Ki67) biomarkers, cell surface adhesion receptor (CD44) and cell division control protein 42 (CDC42). Cytoplasmic MMP9 expression was an independent prognostic factor associated with shorter BC-specific survival. In the external validation cohorts, MMP9 expression was also associated with poor patients' outcome. Transcriptomic analysis confirmed a positive association between MMP9 and ECM remodelling biomarkers. GSEA analysis supports MMP9 association with ECM and cytoskeletal pathways. Conclusion This study provides evidence for the prognostic value of MMP9 in BC. Further functional studies to decipher the role of MMP9 and its association with cytoskeletal modulators in BC progression are warranted. Keywords MMP9 • Breast cancer • ECM remodelling • Prognosis Abbreviations BC Breast cancer BCSS BC-specific survival CI Confidence intervals DGE Differential gene expression ER Oestrogen HR Hazard ratio HER2 Human epidermal growth factor receptor 2 METABRIC Molecular taxonomy of breast cancer international consortium NPI Nottingham Prognostic Index PR Progesterone

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Association Between Ligands and Receptors Related to the Progression of Early Breast Cancer in Tumor Epithelial and Stromal Cells

Cited by 17 publications

References 38 publications

Osteoprotegerin rich tumor microenvironment: implications in breast cancer

Osteoprotegerin rich tumor microenvironment: implications in breast cancer

Prognostic significance of TRAIL-R3 and CCR-2 expression in tumor epithelial cells of patients with early breast cancer

Elevated MMP9 expression in breast cancer is a predictor of shorter patient survival

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