Targeting tumor angiogenesis is a promising alternative strategy for improvement of breast cancer therapy. Robo4 (roundabout homolog 4) signaling has been shown to protect endothelial integrity during sepsis shock and arthritis, and inhibit Vascular Endothelial Growth Factor (VEGF) signaling during pathological angiogenesis of retinopathy, which indicates that Robo4 might be a potential target for angiogenesis in breast cancer. In this study, we used immune competent Robo4 knockout mouse model to show that endothelial Robo4 is important for suppressing breast cancer growth and metastasis. And this effect does not involve the function of Robo4 on hematopoietic stem cells. Robo4 inhibits breast cancer growth and metastasis by regulating tumor angiogenesis, endothelial leakage and tight junction protein zona occuldens protein - 1 (ZO-1) downregulation. Treatment with SecinH3, a small molecule drug which deactivates ARF6 downstream of Robo4, can enhance Robo4 signaling and thus inhibit breast cancer growth and metastasis. SecinH3 mediated its effect by reducing tumor angiogenesis rather than directly affecting cancer cell proliferation. In conclusion, endothelial Robo4 signaling is important for suppressing breast cancer growth and metastasis, and it can be targeted (enhanced) by administrating a small molecular drug.
IntroductionS100A7 (Psoriasin) is an inflammatory protein known to be upregulated in breast cancer. However, the role of S100A7 in breast cancer has been elusive, since both pro- and anti-proliferative roles have been reported in different types of breast cancer cells and animal models. To date, the mechanism by which S100A7 differentially regulates breast cancer cell proliferation is still not clear.MethodsWe used Gene Functional Enrichment Analysis to search for the determining factor of S100A7 differential regulation. We confirmed the factor and elaborated its regulating mechanism using in vitro cell culture. We further verified the findings using xenografts of human breast cancer cells in nude mice.ResultsIn the present study, we show that S100A7 significantly downregulates the expression of miR-29b in Estrogen Receptor (ER)-positive breast cancer cells (represented by MCF7), and significantly upregulates miR-29b in ER-negative cells (represented by MDA-MB-231). The differential regulation of miR-29b by S100A7 in ER-positive and ER-negative breast cancer is supported by the gene expression analysis of TCGA invasive breast cancer dataset. miR-29b transcription is inhibited by NF-κB, and NF-κB activation is differentially regulated by S100A7 in ER-positive and ER-negative breast cancer cells. This further leads to differential regulation of PI3K p85α and CDC42 expression, p53 activation and p53-associated anti-proliferative pathways. Reversing the S100A7-caused changes of miR-29b expression by transfecting exogenous miR-29b or miR-29b-Decoy can inhibit the effects of S100A7 on in vitro cell proliferation and tumor growth in nude mice.ConclusionsThe distinct modulations of the NF-κB – miR-29b – p53 pathway make S100A7 an oncogene in ER-negative and a cancer-suppressing gene in ER-positive breast cancer cells, with miR-29b being the determining regulatory factor.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-014-0275-z) contains supplementary material, which is available to authorized users.
The role of commensal bacterial microbiota in the pathogenesis of human malignancies has been a research field of incomparable progress in recent years. Although breast tissue is commonly assumed to be sterile, recent studies suggest that human breast tissue may contain a bacterial microbiota. In this study, we used an immune-competent orthotopic breast cancer mouse model to explore the existence of a unique and independent bacterial microbiota in breast tumors. We observed some similarities in breast cancer microbiota with skin; however, breast tumor microbiota was mainly enriched with gram-negative bacteria, serving as a primary source of lipopolysaccharide (LPS). In addition, dextran sulfate sodium (DSS) treatment in late-stage tumor lesions increased LPS levels in the breast tissue environment. We also discovered an increased expression of S100A7 and low level of TLR4 in late-stage tumors with or without DSS as compared to early-stage tumor lesions. The treatment of breast cancer cells with LPS increased the expression of S100A7 in breast
Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic cause of adult T-cell leukemia/lymphoma (ATL) and encodes a viral oncoprotein (Hbz) that is consistently expressed in asymptomatic carriers and ATL patients, suggesting its importance in the development and maintenance of HTLV-1 leukemic cells. Our previous work found Hbz protein is dispensable for virus-mediated T-cell immortalization but enhances viral persistence. We and others have also shown that hbz mRNA promotes T-cell proliferation. In our current studies, we evaluated the role of hbz mRNA on HTLV-1-mediated immortalization in vitro as well as in vivo persistence and disease development. We generated mutant proviral clones to examine the individual contributions of hbz mRNA, hbz mRNA secondary structure (stem-loop), and Hbz protein. Wild-type (WT) and all mutant viruses produced virions and immortalized T-cells in vitro. Viral persistence and disease development were also evaluated in vivo by infection of a rabbit model and humanized immune system (HIS) mice, respectively. Proviral load and sense and antisense viral gene expression were significantly lower in rabbits infected with mutant viruses lacking Hbz protein compared to WT or virus with an altered hbz mRNA stem-loop (M3 mutant). HIS mice infected with Hbz protein-deficient viruses showed significantly increased survival times compared to animals infected with WT or M3 mutant virus. Altered hbz mRNA secondary structure, or loss of hbz mRNA or protein, has no significant effect on T-cell immortalization induced by HTLV-1 in vitro; however, the Hbz protein plays a critical role in establishing viral persistence and leukemogenesis in vivo.
Introduction While it is accepted that inflammation is a key component of cancer development, the intricate mechanism linking the two are not fully defined. Unparalleled progress has been underway to provide better understanding of this mechanism. We investigate the role of bacterial microbiota in promoting an inflammatory environment through the induction of the pro-inflammatory molecule, S100A7, and its activation of STAT-3 signaling pathways to promote tumor growth and metastasis in breast cancer (BC). Methods Immune-competent mouse models of orthotopic breast cancer was used to identify and characterize populations of bacterial microbiota in the cancerous breast tissue at tumor onset. Isolated tissues were homogenized and cultured, then processed for DNA extraction. Bacterial species were identified by aligning the sequences on NCBI BLAST. Mouse mammary tissue and tumors were analyzed for S100a7 after intraperitoneal exposure to LPS after cancer cell injections. Isolated tissues were analyzed by IHC, Western Blot analysis and real time RT-PCR. mRNA and Protein expression using real time PCR, western blot and flow cytometry, and binding assays analyzed expression and affinity of LPS/S100A7/TLR4 in BC cell lines in vitro under varying conditions. Protein expression and In vitro functional assays including matrigel invasion and wound closure assays determined the effect of LPS/S100A7 on TLR4 and STAT-3 expression and signaling pathways in promoting tumor invasiveness. Results We observed microbiota in cancerous breast tissue, which is predominantly composed of Gram-negative bacteria at tumor onset. The population of mainly gram negative bacteria at tumor initiation is unique from those populations from feces and skin. This suggests that breast tissue microbiota may be a potential source of LPS in breast tumors. Stimulation with LPS induces secretion/expression of S100A7 in mouse mammary tissue and tumors, as well as BC cell lines. Furthermore, inhibition of LPS by polymixin B decreases S100A7 to basal levels in BC cell lines. LPS/S100A7 combinational treatment has an additive effect on the invasive potential induced by LPS in BC cell lines as shown by invasion assays and wound closure assays. S100A7 over expression increases TLR4 expression as observed by TLR4 mRNA by real time PCR and protein by flow cytometry. Furthermore, secreted S100A7 protein promotes interaction between S100A7 protein and TLR4 receptor in cell lines with endogenous TLR4 expression. In addition, both S100A7 and LPS stimulation of TLR4 can activate STAT3 signaling pathway, and inhibition of either S100A7 and or TLR4 impairs the invasiveness of BC cell lines. Conclusion A unique population of gram negative bacteria characterizes breast cancer tissues. LPS of bacterial cells walls, representative of gram negative bacteria induces S100A7, which interacts with TLR4 to activate the STAT-3 pathway in tumors. This LPS-S100A7-TLR4-STAT3 axis in turn increases the invasiveness of tumor cells to promote tumor metastasis. This suggests that microbiota plays an important role in the initiation and progression of breast cancer through regulation of the pro-inflammatory molecule S100A7. Citation Format: Wilkie T, Zhao H, Nasser M, Ahirwar D, Mishra S, Satoskar A, Pancholi V, Ganju R. The role of S100A7 in microbiota mediated inflammation and breast cancer progression [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-01-19.
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