Elevated CXCL1 expression in breast cancer stroma predicts poor prognosis and is inversely associated with expression of TGF-β signaling proteins

Zou, An; Lambert, Diana; Yeh, Hung‐Wen; Yasukawa, Ken; Behbod, Fariba; Fan, Fang; Cheng, Nikki

doi:10.1186/1471-2407-14-781

Cited by 79 publications

(81 citation statements)

References 81 publications

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“…Cancer associated fibroblasts were isolated from invasive breast ductal carcinoma and characterized in previous studies [95, 96]. DCIS.com cells were generously provided by Fariba Behbod, PharmD, Ph.D (University of Kansas Medical Center).…”

Section: Methodsmentioning

confidence: 99%

Targeted gene silencing of CCL2 inhibits triple negative breast cancer progression by blocking cancer stem cell renewal and M2 macrophage recruitment

et al. 2016

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Triple negative breast cancers are an aggressive subtype of breast cancer, characterized by the lack of estrogen receptor, progesterone receptor and Her2 expression. Triple negative breast cancers are non-responsive to conventional anti-hormonal and Her2 targeted therapies, making it necessary to identify new molecular targets for therapy. The chemokine CCL2 is overexpressed in invasive breast cancers, and regulates breast cancer progression through multiple mechanisms. With few approaches to target CCL2 activity, its value as a therapeutic target is unclear. In these studies, we developed a novel gene silencing approach that involves complexing siRNAs to TAT cell penetrating peptides (Ca-TAT) through non-covalent calcium cross-linking. Ca-TAT/siRNA complexes penetrated 3D collagen cultures of breast cancer cells and inhibited CCL2 expression more effectively than conventional antibody neutralization. Ca-TAT/siRNA complexes targeting CCL2 were delivered to mice bearing MDA-MB-231 breast tumor xenografts. In vivo CCL2 gene silencing inhibited primary tumor growth and metastasis, associated with a reduction in cancer stem cell renewal and recruitment of M2 macrophages. These studies are the first to demonstrate that targeting CCL2 expression in vivo may be a viable therapeutic approach to treating triple negative breast cancer.

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Section: Methodsmentioning

confidence: 99%

Targeted gene silencing of CCL2 inhibits triple negative breast cancer progression by blocking cancer stem cell renewal and M2 macrophage recruitment

et al. 2016

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“…CXCL1 has neutrophil chemoattractant activity, is a potent angiogenic factor, and is expressed by macrophages, neutrophils and epithelial cells [133,134]. Neutrophil granulocytes also regulate stromal interactions and were associated with worse prognoses in both breast and gastric cancers [135,136].…”

Section: In Vitro and In Vivo Evidencementioning

confidence: 99%

Somatic Mutation Theory - Why it's Wrong for Most Cancers

Brücher¹,

Jamall

2016

Cell Physiol Biochem

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Hysteron proteron reverses both temporal and logical order and this syllogism occurs in carcinogenesis and the somatic mutation theory (SMT): the first (somatic mutation) occurs only after the second (onset of cancer) and, therefore, observed somatic mutations in most cancers appear well after the early cues of carcinogenesis are in place. It is no accident that mutations are increasingly being questioned as the causal event in the origin of the vast majority of cancers as clinical data show little support for this theory when compared against the metrics of patient outcomes. Ever since the discovery of the double helical structure of DNA, virtually all chronic diseases came to be viewed as causally linked to one degree or another to mutations, even though we now know that genes are not simply blueprints, but rather an assemblage of alphabets that can, under non-genetic influences, be used to assemble a business letter or a work of Shakespearean literature. A minority of all cancers is indeed caused by mutations but the SMT has been applied to all cancers, and even to chemical carcinogenesis, in the absence of hard evidence of causality. Herein, we review the 100 year story of SMT and aspects that show why genes are not just blueprints, how radiation and mutation are associated in a more nuanced view, the proposed risk of cancer and bad luck, and the in vitro and in vivo evidence for a new cancer paradigm. This paradigm is scientifically applicable for the majority of non-heritable cancers and consists of a six-step sequence for the origin of cancer. This new cancer paradigm proclaims that somatic mutations are epiphenomena or later events occurring after carcinogenesis is already underway. This serves not just as a plausible alternative to SMT and explains the origin of the majority of cancers, but also provides opportunities for early interventions and prevention of the onset of cancer as a disease.

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“…To quantify protein expression, we utilized an Image J softwarebased approach. 38 This method is low cost, freely available and would result in yield continuous values, possibly reducing the subjectivity commonly found in scoring. 39 Expression patterns were compared among normal breast tissues, fibroadenoma tissues, which are non-malignant breast lesions, and invasive breast carcinoma tissues.…”

Section: Ccl2 and Fsp1 Are Co-expressed In Breast Cancermentioning

confidence: 99%

“…Software analysis of biomarker expression in breast tissues was performed using methods previously described. 38 Images were first imported into Adobe Photoshop. Color and exposure of images were normalized using auto-contrast.…”

Section: Image Quantificationmentioning

confidence: 99%

Elevated expression of chemokine C-C ligand 2 in stroma is associated with recurrent basal-like breast cancers

Yao

Staggs

et al. 2016

Modern Pathology

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Despite advances in treatment, up to 30% of breast cancer patients experience disease recurrence accompanied by more aggressive disease and poorer prognosis. Treatment of breast cancer is complicated by the presence of multiple breast cancer subtypes, including: luminal, Her2 overexpressing, and aggressive basal-like breast cancers. Identifying new biomarkers specific to breast cancer subtypes could enhance the prediction of patient prognosis and contribute to improved treatment strategies. The microenvironment influences breast cancer progression through expression of growth factors, angiogenic factors and other soluble proteins. In particular, chemokine C-C ligand 2 (CCL2) regulates macrophage recruitment to primary tumors and signals to cancer cells to promote breast tumor progression. Here we employed a software-based approach to evaluate the prognostic significance of CCL2 protein expression in breast cancer subtypes in relation to its expression in the epithelium or stroma or in relation to fibroblast-specific protein 1 (Fsp1), a mesenchymal marker. Immunohistochemistry analysis of tissue microarrays revealed that CCL2 significantly correlated with Fsp1 expression in the stroma and tumor epithelium of invasive ductal carcinoma. In the overall cohort of invasive ductal carcinomas (n = 427), CCL2 and Fsp1 expression in whole tissues, stroma and epithelium were inversely associated with cancer stage and tumor size. When factoring in molecular subtype, stromal CCL2 was observed to be most highly expressed in basal-like breast cancers. By Cox regression modeling, stromal CCL2, but not epithelial CCL2, expression was significantly associated with decreased recurrence-free survival. Furthermore, stromal CCL2 (HR = 7.51 P = 0.007) was associated with a greater hazard than cancer stage (HR = 2.45, P = 0.048) in multivariate analysis. These studies indicate that stromal CCL2 is associated with decreased recurrence-free survival in patients with basal-like breast cancer, with important implications on the use of stromal markers for predicting patient prognosis.

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Elevated CXCL1 expression in breast cancer stroma predicts poor prognosis and is inversely associated with expression of TGF-β signaling proteins

Cited by 79 publications

References 81 publications

Targeted gene silencing of CCL2 inhibits triple negative breast cancer progression by blocking cancer stem cell renewal and M2 macrophage recruitment

Targeted gene silencing of CCL2 inhibits triple negative breast cancer progression by blocking cancer stem cell renewal and M2 macrophage recruitment

Somatic Mutation Theory - Why it's Wrong for Most Cancers

Elevated expression of chemokine C-C ligand 2 in stroma is associated with recurrent basal-like breast cancers

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