AV ES and TKK collected clinical information. p-Akt Thr308expression had strong unfavorable effect in men only (P = 0.009). In contrast, p-Akt Ser473expression had strong unfavorable impact in women (P = 0.023). PgR-/p-Akt Ser473+ phenotype tended to have less favorable impact in women (P = 0.087), but was the most favorable one in men (P = 0.010). == Conclusion == Expression of PI3K was significantly associated with aggressive behavior and shorter DSS in non-GIST STSs. The site of Akt Macitentan (n-butyl analogue) phosphorylation seems to have gender-dependent impact on survival in STS patients. Keywords:soft tissue sarcomas, Akt isoforms, PI3K, PTEN, ER, PgR, disease-specific survival == Background == Soft tissue sarcomas (STS) are malignant tumors arising from extraskeletal connective tissues. They are heterogeneous neoplasms, GNAS consisting Macitentan (n-butyl analogue) of more than 50 subtypes, and comprise less than 1% of adult malignancies [1,2]. Approximately 50% of the STS patients will succumb to their disease because of metastasis or local progression [3]. The prognostic factors determining tumor evolution and ultimately patients’ fate include tumor grade, size, location, depth, histological entity, Macitentan (n-butyl analogue) positive resection margins and presence of local relapse [4-10]. In addition, an array of recurrent gene aberrations are found to be prognostic and predictive biomarkers in STSs [11-13]. Akt is usually a serine/threonine protein kinase that exists in three possible isoforms, including Akt1, Akt2, and Akt3. Akt can be activated by phosphorylation at threonine308or at serine473for Akt1 or homologous sites for Akt2 and Akt3 by phosphatases which along with Akt isoforms, belong to the phosphoinositide 3-kinase (PI3K)/Akt pathway. The PI3K/Akt pathway has been linked to an extraordinarily diverse group of cellular functions, including cell growth, proliferation, differentiation, motility, survival, intracellular trafficking and angiogenesis [14]. Both PI3K and Akt isoforms have been implicated as major players in many types of cancer [15-17]. The PI3K/Akt pathway seems to be more often deregulated in cancer than any other pathway [18]. However, in the literature there is disagreement regarding the prognostic impact of Akt expression. While the majority of studies agree that Akt expression overtly indicates a poor prognosis [19-21], there are several studies showing the opposite effect [22,23]. Expressions of PI3K/Akt pathway components have rarely been investigated in STSs and there are almost no studies devoted to their prognostic value [24]. Different physiological function of the Akt family kinases implies that the expression of its isoforms may also have different prognostic impact in cancer. The significance of this variation for the survival of the STS patients is not well investigated and it is not clear whether the site of phosphorylation and the pattern of expression can play prognostic roles. In previous studies, we have shown the prognostic value of female steroid hormone receptors in STSs, both alone and in the coexpression with TGF- and fascin [25,26]. Such prognostic impact is not surprising, since both ER and PgR regulate growth and cell differentiation upon ligand-dependent and ligand-independent activation and are in essence growth factors. In this context we wanted to explore the correlations between female hormone receptors and the members of PI3K/Akt signaling pathway. To our knowledge, these correlations have not been described previously. In this study, we investigate the prognostic impact of all isoforms of Akt (phosphorylated at threonine308and Akt phosphorylated at serine473, non-phosphorylated Akt2, and total Akt3), PI3K, PTEN, ER and PgR in 249 non-GIST.