Ser etnógrafa: identidad y reflexividad

STAT1 was the first STAT protein to be discovered and is mainly activated in response to Type I and II IFNs, and upon activation of their receptors, STAT1 mediates the transcription of genes encoding proteins with anti-proliferative, anti-viral and immune regulatory properties. The activity of STAT1 is controlled by phosphorylation at pY 701 and pS 727 within the transactivation domain of the protein (Darnell et al., 1997; Buettner et al., 2002; Yu et al., 2004; Schindlr et al., 2007; Stark and Darnell, 2012).

Several lines of evidence implicate STAT1 as an anti-proliferative and a pro-apoptotic molecule. Early studies, using mouse models, demonstrated that STAT1-deleted mice were more susceptible to tumour development than controls (Kaplan et al., 1998, Shankaran et al., 2001). Activation of STAT1, in response to IFN-γ, has been shown to be associated with inhibition of proliferation of both mouse and human tumour cells via up- regulation of cyclin-dependent kinase inhibitor p21 expression and down-regulation of c- Myc promoter expression (Ramana et al., 2000). In addition, STAT1 induces apoptosis by up-regulation of caspases 2 and 3 expression or the expression of inducible nitric oxide

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61 synthase (Battle and Frank, 2002; Kim and Lee, 2007). The suppressing role of STAT1 in cancer is further supported by its ability to inhibit angiogenesis and tumour metastasis in mouse models (Huang et al., 2002).

STAT1 as a key transcriptional factor of IFN signalling plays an important role in innate immune response by protecting the host from virus infections and other pathogens (Schindlr et al., 2007; Stark and Darnell, 2012). IFNs signal through STAT1 do not only increase anti-tumour immune responses through the activation of natural killer cells and macrophages but also through activation of adaptive immune mediators; TH1 and cytotoxic CD8+T-lymphocytes (Yu et al., 2009).

Targeted disruption of STAT1 results in viable mice with compromised innate immunity and are highly susceptible to infection (Durbin et al., 1996; Meraz et al., 1996). In addition, lack of STAT1 significantly increases the incidence of spontaneous mammary tumour development in mice (Schneckenleithne et al., 2011). The increased rate of tumour formation in STAT1 deficient mice (STAT1−/−) was previously attributed to impaired immune surveillance of tumours because these mice failed to respond to IFN-γ and displayed reduced natural killer activity (Dunn et al., 2006). In turn, lack of STAT1 could potentially promote tumour cell survival due to the loss of IFN-dependent tumour surveillance system (Buettner et al., 2002).

Recent evidence for the role of STAT1 in the tumour microenvironment has further supported the immune surveillance role in breast cancer. Using immunohistochemistry in a large cohort of patients, selective down-regulation of STAT1 protein was more prominent in the tumour cells compared with the surrounding stroma and infiltrating lymphocytes (Chan et al., 2012). In addition, STAT1 sustained efficient cytotoxic T- lymphocyte mediated immune response and was essential for full functioning CD8+

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62 cytotoxicity (Schneckenleithne et al., 2011). Thus, the ability of STAT1 to control the function of immune cells may play a crucial role in regulation of tumourigenesis.

In normal circumstances, STAT1 is regulated during the different stages of mammary gland development and its expression and activity is detected only in virgin animals, or during early pregnancy and late involution (Watson, 2001), but not through pregnancy and lactation (Philp et al., 1996).

Recent studies, using different experimental approaches, support the anti-tumour function of STAT1 in mammary tumourigenesis (Klover et al., 2010; Raven et al., 2011; Chan et al., 2012). Tumour initiated by Her-2 in STAT1−/− female mice developed breast tumours ~6 weeks earlier than their STAT1+/+ counterparts (Ravan et al., 2011) and the overall disease latency was significantly enhanced in STAT1-deficient mice being 49.4 weeks compared with 62.4 weeks in STAT1-proficient animals (Klover et al., 2010). Non- tumourigenic and tumourigenic mammary epithelial STAT1−/−cells in vivo were capable of increasing proliferation rate and were found to form significantly thicker mammosphere layers in the mammary acini (Schneckenleithne et al., 2011). In addition, Chan and colleagues demonstrated that STAT1 deficient mice spontaneously developed mammary adenocarcinomas displaying ER +ve / PR +v tumour cells similar to that of human luminal breast cancer, and that STAT1 expression was frequently lost during breast cancer progression. Induction of wildtype STAT1 into STAT1 deficient mammary tumour cells lead to apoptosis (Chan et al., 2012), indicating a cell autonomous or a tumour cell-specific function of STAT1 independent of STAT1-mediated transcription. Furthermore, the anti- tumour activity of the milk protein α-casein, in preventing breast cancer growth and metastases has been found to require activation of STAT1 (Bonuccelli et al., 2012).

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63 However, STAT1 has been also implicated in cancer development including mammary tumours. This is based on the observation that total and phosphorylated STAT1 (ph- STAT1) is elevated in human breast cancer (Widschwendter et al., 2002; Sheen-Chen et al., 2007; Yau et al., 2010; Magkou et al., 2012) and is associated with variable prognostic outcomes. STAT1 DNA binding activity and Y705 phosphorylation in invasive breast carcinomas was associated with improved survival independent of other prognostic variables (Widschwendter et al., 2002). Increased STAT1 mRNA levels were shown to be part of a molecular signature associated with better prediction of the metastatic outcome for patients with hormone receptor negative and triple negative breast cancers (Yau et al., 2010). In contrast, assessment of STAT1 levels by Charpin and colleagues in larger cohort, reported an association between STAT1 expression and worse survival (Charpin et al., 2009). Also, ph-STAT1 was associated with advanced stage and worse survival in premenopausal women (Magkou et al., 2012). However, one report, using total STAT1 protein, found no association between level of total STAT1 and breast cancer survival (Sheen-Chen et al., 2007).

Overall, it is clear that a conclusion about the prognostic value of STAT1 in breast cancer cannot be made due to rarity and inconsistency of evidence available.

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