Expression of cytokine messenger RNA in normal and neoplastic human breast tissue: Identification of interleukin‐8 as a potential regulatory factor in breast tumours

Green, Andrew; Green, Victoria L.; White, Michael C.; Speirs, Valerie

doi:10.1002/(sici)1097-0215(19970917)72:6<937::aid-ijc3>3.3.co;2-a

Cited by 16 publications

(25 citation statements)

References 12 publications

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“…The importance of IL-8 as a proangiogenic factor has been documented in breast cancers (Green et al, 1997;De Larco et al, 2001;Freund et al, 2003;Sparmann and Bar-Sagi, 2004). Development of therapeutic molecules targeting IL-8 and/or human IL-8 receptors seems necessary for treatment of tumors that overexpress HER2, as we found a positive correlation between IL-8 expression and HER2 expression in this study.…”

Section: Discussionmentioning

confidence: 99%

“…IL-8 was subsequently found to promote the growth and metastasis of tumors, in part by stimulating angiogenesis (Green et al, 1997;Bar-Eli, 1999;De Larco et al, 2001;Rofstad and halsor, 2002;Chen et al, 2003;Freund et al, 2003;Benoy et al, 2004). Both tumor cells and tumorassociated neutrophils and macrophages have been reported to release IL-8, which contributes to accelerated tumor growth and poor survival (Chen et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

“…Hypoxia in solid tumors also stimulates the expression of both IL-8 and VEGF, and VEGF can further enhance IL-8 expression (Rofstad and Halsor, 2002). IL-8 overexpression is associated with high metastatic potential in breast cancers (Green et al, 1997;De Larco et al, 2001;Freund et al, 2003). IL-8 serum levels are increased in patients with breast cancers and are an independent prognostic factor for survival (Benoy et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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HER2 signaling modulates the equilibrium between pro- and antiangiogenic factors via distinct pathways: implications for HER2-targeted antibody therapy

et al. 2006

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We determined the impact of HER2 signaling on two proangiogenic factors, vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8), and on an antiangiogenic factor, thrombospondin-1 (TSP-1). Re-expression of HER2 in MCF-7 and T-47D breast cancer cells that endogenously express low levels of HER2 resulted in elevated expression of VEGF and IL-8 and decreased expression of TSP-1. Inhibition of HER2 with a humanized anti-HER2 antibody (trastuzumab, or Herceptin s ) or a retrovirus-mediated small interfering RNA against HER2 (siHER2) decreased VEGF and IL-8 expression, but increased TSP-1 expression in BT474 breast cancer cells that express high levels of HER2. These in vitro results were further evaluated by treatment of BT474 xenografts in immunosuppressed mice with trastuzumab. Trastuzumab inhibited growth of BT474 xenografts and decreased microvascular density associated with downregulation of VEGF and IL-8 and with upregulation of TSP-1 expression. Inhibiting the PI3K-AKT pathway decreased VEGF and IL-8 expression. AKT1 overexpession increased VEGF and IL-8 expression, but did not increase TSP-1 expression. A p38 kinase inhibitor, SB203580, instead blocked TSP-1 expression and a p38 activator, MKK6, increased TSP-1 expression. Trastuzumab stimulated sustained p38 activation and SB203580 attenuated the TSP-1 upregulation induced by trastuzumab. HER2 signaling therefore influences the equilibrium between pro-and antiangiogenic factors via distinct signaling pathways. Trastuzumab inhibits angiogenesis and tumor growth, at least in part, through activation of the HER2-p38-TSP-1 pathway and inhibition of the HER2-PI3K-AKT-VEGF/IL-8 pathway.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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HER2 signaling modulates the equilibrium between pro- and antiangiogenic factors via distinct pathways: implications for HER2-targeted antibody therapy

et al. 2006

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“…For the oxidative pathway, the reverse was true with this pathway superior in cultures derived from normal rather than malignant breast. variety of cell and molecular biology studies (Speirs et al, 1996a;Green et al, 1997). These cultures retain many of the characteristics associated with breast tumours in vivo, particularly the presence of functional ER and a high level of reductive 17-HSD, an enzyme involved in steroid biosynthesis whose activity is up-regulated in breast tumours (Vermeulen et al, 1986;Peltoketo et al, 1996).…”

Section: Genetic Analysismentioning

confidence: 99%

Short-term primary culture of epithelial cells derived from human breast tumours

Speirs

Green²,

Walton³

et al. 1998

Br J Cancer

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Summary As experimental models for breast cancer, most studies rely on established human breast cancer cell lines. However, many of these lines were established over 20 years ago, many from pleural effusions rather than the primary tumour, so the validity of using them as representative models is questionable. This paper describes our experiences, over a 3-year period, in establishing short-term epithelial-cellenriched preparations from primary breast tumours based on differential centrifugation followed by culture in selective media. Epithelial cells were successfully cultured from 55% of samples, but culture success did not appear to be correlated with tumour histology, stage, grade or node status. Epithelial cell-enriched cultures were immunopositive for broad-spectrum cytokeratin and epithelial membrane antigen (EMA). Positivity for keratin 19 confirmed that the cultures contained tumour-derived cells, which additionally showed significantly higher activity of the reductive pathway of the steroid-converting enzyme 17p-hydroxysteroid dehydrogenase type 1. That the cultures contained tumour and not normal epithelial cells was further substantiated by the complete absence of the calmodulin-like gene NB-1 in tumour-derived cultures; this is only associated with normal breast epithelia. Eighty-five per cent of cultures established from oestrogen receptor (ER)-positive tumours expressed ER in vitro; this was functional in 66% of cultures, although ER-positive phenotype was gradually lost over time. In conclusion, epithelial cells can be isolated and maintained as short-term cultures from primary breast tumours irrespective of histopathological or clinical details, providing a model system with a greater biological and clinical relevance than breast cancer cell lines.

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“…These small proteins, including interleukin-1 beta (IL-1β), IL-6, IL-8, and tumor necrosis fac-component of a paracrine/autocrine communication network in the mammary gland throughout the different stages of pregnancy and parturition [25,44]. It should be noted that a low constitutive production of some of these cytokines may take place in healthy individuals [22,23,55].…”

Section: Introductionmentioning

confidence: 99%

Morphometric analysis of proinflammatory cytokines in mammary glands of sows suggests an association between clinical mastitis and local production of IL-1beta, IL-6 and TNF-alpha

et al. 2007

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-Twelve healthy primiparous sows received intramammary inoculation with Escherichia coli (serotype O127) during the 24-h period preceding parturition. Mammary gland biopsy samples were taken immediately before inoculation (0 h) and from the inoculated and the contralateral noninoculated glands 24 h after inoculation. The analyses of interleukin-1 beta (IL-1β), IL-6, IL-8, and tumor necrosis factor alpha (TNF-α) by immunohistochemistry revealed that the production of these proinflammatory cytokines significantly increased in the inoculated mammary glands of sows that developed clinical signs of mastitis (affected group, n = 4) 24 h after inoculation. This was also true for IL-8 in the inoculated mammary glands of sows that did not develop clinical signs of mastitis (nonaffected group, n = 8). Sows that developed clinical signs of mastitis displayed significantly lower constitutive production of IL-1β than did sows that remained clinically healthy. The data indicate that the development of clinical symptoms of coliform mastitis in the sow is associated with a locally increased proinflammatory cytokine production in response to intramammary E. coli infection.cytokine / immunohistochemistry / mastitis / pig / E. coli

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Expression of cytokine messenger RNA in normal and neoplastic human breast tissue: Identification of interleukin‐8 as a potential regulatory factor in breast tumours

Cited by 16 publications

References 12 publications

HER2 signaling modulates the equilibrium between pro- and antiangiogenic factors via distinct pathways: implications for HER2-targeted antibody therapy

HER2 signaling modulates the equilibrium between pro- and antiangiogenic factors via distinct pathways: implications for HER2-targeted antibody therapy

Short-term primary culture of epithelial cells derived from human breast tumours

Morphometric analysis of proinflammatory cytokines in mammary glands of sows suggests an association between clinical mastitis and local production of IL-1beta, IL-6 and TNF-alpha

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