interleukin-8 and Carcinoma--Ductal--Breast

Formation of metastases, also known as cancer dissemination, is an important stage of breast cancer (BrCa) development. KISS1 expression is associated with inhibition of metastases development. Recently we have demonstrated that BrCa metastases to the brain exhibit low levels of KISS1 expression at both mRNA and protein levels. By using multicolor immunofluorescence and coculture techniques here we show that normal adult astrocytes in the brain are capable of promoting metastatic transformation of circulating breast cancer cells localized to the brain through secretion of chemokine CXCL12. The latter was found in this study to downregulate KISS1 expression at the post-transcriptional level via induction of microRNA-345 (MIR345). Furthermore, we demonstrated that ectopic expression of KISS1 downregulates ATG5 and ATG7, 2 key modulators of autophagy, and works concurrently with autophagy inhibitors, thereby implicating autophagy in the mechanism of KISS1-mediated BrCa metastatic transformation. We also found that expression of KISS1 in human breast tumor specimens inversely correlates with that of MMP9 and IL8, implicated in the mechanism of metastatic invasion, thereby supporting the role of KISS1 as a potential regulator of BrCa metastatic invasion in the brain. This conclusion is further supported by the ability of KISS1, ectopically overexpressed from an adenoviral vector in MDA-MB-231Br cells with silenced expression of the endogenous gene, to revert invasive phenotype of those cells. Taken together, our results strongly suggest that human adult astrocytes can promote brain invasion of the brain-localized circulating breast cancer cells by upregulating autophagy signaling pathways via the CXCL12-MIR345- KISS1 axis.

Topics: Adult; Aged; Animals; Astrocytes; Autophagy; Autophagy-Related Protein 5; Autophagy-Related Protein 7; Brain Neoplasms; Breast Neoplasms; Carcinoma, Ductal, Breast; Cell Line, Tumor; Chemokine CXCL12; Female; Humans; Interleukin-8; Kisspeptins; Matrix Metalloproteinase 9; Mice; Microglia; MicroRNAs; Middle Aged; Xenograft Model Antitumor Assays

Cancer progression and metastasis are complex processes, dependent of molecules involved in inflammation, degradation and invasion. These molecules can be used as prognostic indicators to single out patients with higher risk of recurrence. Interleukin-8 (IL-8) has a role in inflammation, urokinase plasminogen activator (uPA), plasminogen activator inhibitor type-1 (PAI-1) and matrix metalloproteinase-2, -9 have a decisive part in the process of degradation and invasion, while vascular endothelial growth factor (VEGF) is consequential for angiogenesis.. Aim of our study is to determine relations between IL-8, uPA, PAI-1, MMP-2, -9, VEGF as their prognostic significance in terms of recurrence free survival.. This study included 91 untreated patients with lymph node negative (N0) primary breast cancer.. Patients with higher levels of uPA (p= 0.05), PAI-1 (0.05), MMP2 (p= 0.05) and IL-8 (p= 0.02) have a poor prognosis. Positive correlations were found between ER - PR, uPA - PAI-1, uPA - MMP9, PAI-1 - IL-8, MMP9 - IL-8, MMP9 - VEGF. Negative correlations were found between ER - IL-8, uPA - IL-8, MMP2 - VEGF.. Higher concentrations of IL-8, uPA, PAI-1 and MMP2, as is MMP9 and VEGF, confirmed aggressive phenotype and poor prognosis in different subgroups.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; Carcinoma, Ductal, Breast; Carcinoma, Lobular; Combined Modality Therapy; Female; Follow-Up Studies; Humans; Immunoenzyme Techniques; Interleukin-8; Lymphatic Metastasis; Mastectomy; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Neoplasm Invasiveness; Neoplasm Recurrence, Local; Neoplasm Staging; Plasminogen Activator Inhibitor 1; Prognosis; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Survival Rate; Urokinase-Type Plasminogen Activator; Vascular Endothelial Growth Factor A

Skeletal metastases of breast cancer and subsequent osteolysis connote a dramatic change in the prognosis for the patient and significantly increase the morbidity associated with disease. The cytokine interleukin 8 (IL-8/CXCL8) is able to directly stimulate osteoclastogenesis and bone resorption in mouse models of breast cancer bone metastasis. In this study, we determined whether circulating levels of IL-8 were associated with increased bone resorption and breast cancer bone metastasis in patients and investigated IL-8 action in vitro and in vivo in mice. Using breast cancer patient plasma (36 patients), we identified significantly elevated IL-8 levels in bone metastasis patients compared with patients lacking bone metastasis (p<0.05), as well as a correlation between plasma IL-8 and increased bone resorption (p<0.05), as measured by NTx levels. In a total of 22 ER+ and 15 ER- primary invasive ductal carcinomas, all cases examined stained positive for IL-8 expression. In vitro, human MDA-MB-231 and MDA-MET breast cancer cell lines secrete two distinct IL-8 isoforms, both of which were found to stimulate osteoclastogenesis. However, the more osteolytic MDA-MET-derived full length IL-8(1-77) had significantly higher potency than the non-osteolytic MDA-MB-231-derived IL-8(6-77), via the CXCR1 receptor. MDA-MET breast cancer cells were injected into the tibia of nude mice and 7days later treated daily with a neutralizing IL-8 monoclonal antibody. All tumor-injected mice receiving no antibody developed large osteolytic bone tumors, whereas 83% of the IL-8 antibody-treated mice had no evidence of tumor at the end of 28days and had significantly increased survival. The pro-osteoclastogenic activity of IL-8 in vivo was confirmed when transgenic mice expressing human IL-8 were examined and found to have a profound osteopenic phenotype, with elevated bone resorption and inherently low bone mass. Collectively, these data suggest that IL-8 plays an important role in breast cancer osteolysis and that anti-IL-8 therapy may be useful in the treatment of the skeletal related events associated with breast cancer.

Topics: Animals; Bone Neoplasms; Bone Screws; Breast Neoplasms; Carcinoma, Ductal, Breast; Cell Line, Tumor; Female; Humans; Interleukin-8; Mice; Mice, Nude; Mice, Transgenic; Osteolysis

Debate about the potential effects that surgery might have on cancer cells dormancy and angiogenesis prompted us to investigate the impact of breast surgery on circulating angiogenesis modulating gene transcripts and proteins.. Blood samples from 10 female patients diagnosed with breast cancer and 6 with fibroadenoma were collected before surgery and post-operatively on days 3 and 7 (breast cancer patients only). A set of 84 angiogenesis-associated transcripts were assessed using quantitative PCR arrays, and circulating protein levels (vascular endothelial growth factor A (VEGFA), IL8 and fibroblast growth factor 2 (FGF2) were measured using ELISA in the same samples. The results were investigated against clinicopathological data and patient outcome.. Plasma levels of VEGFA and IL8 after surgery were significantly elevated in the breast cancer group compared to the control group (P = 0.038 and P = 0.021, respectively). In the cohort of breast cancer patients, VEGFA increased on day 3 (P = 0.038) and declined on day 7 (P= 0.017), while IL8 did not change on day 3 but showed a significant decline on day 7 (P = 0.02). FGF2 levels did not change significantly over time. Regarding gene transcripts, we detected upregulation of a significant number of angiogenesis-specific genes in patients with breast cancer versus controls: sphingosine kinase 1(SPHK1), epidermal growth factor (EGF), vascular endothelial growth factor C (VEGFC), neuropilin 1 (NRP1), fibroblast growth factor (FGF1), laminin alpha 5 (LAMA5), collagen type IV alpha 3 (COL4A3), IL8, ephrin B2 (EFNB2), ephrin A3 (EFNA3), tyrosine endothelial kinase (TEK), integrin beta 3 (ITGB3), AKT1, thrombospondin 1 (THBS1), chemokine (C-C motif) ligand 11 (CCL11) and TIMP metallopeptidase inhibitor 3 (TIMP3). Surgery induced an altered expression in several keygenes in breast cancer patients. We identified an upregulation of COL4A3 and downregulation of chemokine (C-X-C motif) ligand 9 (CXCL9), EGF, FGF1, Kinase insert domain receptor (KDR), Placental growth factor (PGF), TIMP3 and VEGFC.. Breast cancer patients have a different expression profile of circulating angiogenesis biomarkers compared to patients with fibroadenoma. Moreover, mastectomy promotes a transient increase of VEGFA and a shift in the expression patterns of a broad panel of angiogenesis-related circulating gene transcripts.

Topics: Adult; Aged; Angiogenic Proteins; Biomarkers, Tumor; Breast Neoplasms; Carcinoma, Ductal, Breast; Case-Control Studies; Enzyme-Linked Immunosorbent Assay; Female; Fibroadenoma; Fibroblast Growth Factor 2; Follow-Up Studies; Humans; Interleukin-8; Longitudinal Studies; Middle Aged; Neoplasm Staging; Prognosis; Prospective Studies; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Vascular Endothelial Growth Factor A

Tumor necrosis factor α (TNF-α) signaling pathways play important roles during tumorigenesis and inflammation. Ubiquitin-dependent processes are central to the regulation of TNF-α and nuclear factor κB (NF-κB) signaling. We performed a targeted siRNA screen for ubiquitin-specific proteases (USPs) and identified USP2 as a modulator of TNF-α-induced NF-κB signaling. We showed that USP2 is required for the phosphorylation of IκB, nuclear translocation of NF-κB and expression of NF-κB-dependent target genes and IL-8 secretion. Our study also provides evidence for isoform-specific functions of USP2. The immunohistochemical analysis of breast carcinomas revealed that USP2 expression is frequently downregulated. Together, our results implicate USP2 as a novel positive regulator of TNF-α-induced NF-κB signaling and show that its expression is altered in tumor cells.

Topics: Breast Neoplasms; Carcinoma, Ductal, Breast; Cell Line, Tumor; Cytokines; Down-Regulation; Endopeptidases; Female; Humans; Interleukin-8; NF-kappa B; RNA Interference; Signal Transduction; Tumor Necrosis Factor-alpha; Ubiquitin Thiolesterase

A case-control study involving 257 breast cancer patients with invasive ductal carcinoma and 233 healthy women was carried out to explore if the IL-8 -251T/A polymorphism and the CXCR2 +1208 C/T polymorphism have a role in breast cancer susceptibility. Genotypic analysis showed an increased frequency of high producer IL-8 -251AA genotype (p=0.016) in the patient group as compared to controls while CXCR2 +1208 C/T polymorphism did not show any differences between studied groups. However, in contrast to IL-8 -251 polymorphism, the percentage of CXCR2 +1208 TT genotype was significantly lower in patients with NPI3.4 (2% and 12%, respectively; p=0.03). Also, ER- tumors showed an approximately significant higher CXCR2 +1208 TT genotype compared to ER+ tumors (18.6% and 7.1%, respectively; p=0.07). In conclusion, IL-8 -251T/A polymorphism is associated with development of invasive ductal carcinoma type of breast cancer while CXCR2 +1208C/T polymorphism may affect the disease progression.

Topics: Adult; Aged; Aged, 80 and over; Breast Neoplasms; Carcinoma, Ductal, Breast; Case-Control Studies; Disease Progression; Female; Genetic Predisposition to Disease; Genotype; Humans; Interleukin-8; Middle Aged; Polymerase Chain Reaction; Polymorphism, Genetic; Receptors, Interleukin-8B

Re-expansion pulmonary edema (REPE) leading to hypoxic respiratory failure and death occurred following a unilateral low-volume (750 ml) thoracentesis in a young patient 8 days after high-dose chemotherapy and autologous stem cell transplantation (HDC/ASCT) for advanced-stage breast cancer. A higher volume (1,000 ml) thoracentesis from the contralateral lung, 2 weeks prior to HDC/ASCT, showed no clinical consequences. We have recently demonstrated increased levels of inflammatory cytokines in the lungs of patients following HDC/ASCT, a finding which may predispose them to exaggerated inflammatory lung injury. In postmortem analysis, this patient's lung demonstrated substantial intra-alveolar edema and marked elevation in interleukin-8, detected by immunohistochemistry. This suggests that patients who have recently undergone HDC/ASCT may be at increased risk for the development of REPE following thoracentesis.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carcinoma, Ductal, Breast; Fatal Outcome; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunohistochemistry; Interleukin-8; Lung; Pulmonary Edema

Virtually pure primary cultures of normal mammary epithelial cells (MEC) obtained from healthy women were shown to release interleukin 6 and 8 (IL6, IL8) and to produce a nonsecreted form of tumor-necrosis factor (TNF). No interferon (IFN), whether alpha, beta, or gamma, or IL1-alpha or -beta could be detected. Analysis of cellular RNA confirmed these findings and showed that MEC also express IL6 receptor and TNF-alpha-related mRNAs. Epithelial cells were selectively stained by antibodies to IL6, IL8 and TNF-alpha both in primary cultures and in the normal mammary gland. Samples of human milk contained sizable amounts of IL6, IL8 and IFN-gamma; yet the liquid phase was consistently negative for other cytokines (i.e., TNF-alpha, IFN-alpha/-beta, IL1-alpha/-beta). Expression of IL6 (but not of IL8 and TNF-alpha) was abolished in ductal infiltrating carcinomas and greatly reduced in cultures of oncogene-transfected mammary cells, suggesting that alterations of IL6 expression are associated with pathogenesis in breast cancer.

Topics: Adolescent; Adult; Breast; Breast Neoplasms; Carcinoma, Ductal, Breast; Cells, Cultured; Epithelium; Female; Humans; Interferon-gamma; Interleukin-6; Interleukin-8; Tumor Necrosis Factor-alpha