Slides were viewed using a BX61 Olympus Microscope supplied with DP50 camera and Viewfinder Lite 1.0 Version (Pixera Corporation) image analysis system. The Kaplan-Meier and Cox regression methods were used for survival assessment and statistical analysis. Results Overall, patients carrying increased expression of pERK1-2 (p (S)-crizotinib = 0.027) and survivin (p = 0.008) proteins as well as amplification of em h-prune /em gene (p = 0.045) presented a statistically-significant poorer overall survival in comparison with cases found negative for such alterations. After multivariate analysis, the pathological response to primary chemotherapy and the survivin overexpression in primary carcinoma represented the main parameters with a role as impartial prognostic factors in our series. Conclusions Although retrospective, our study identified some molecular parameters with a significant impact on prediction of the response to therapy or prognosis among T4 breast cancer patients. Further large prospective studies are needed in order to validate the use of such markers for the management of these patients. Background Since the staging systems of breast cancer were introduced during the course of the last century, the involvement of the skin has always been considered a morphologic characteristic leading to the classification of the tumour into the highest non-metastatic disease stage. In the current edition of the International Union Against Cancer (UICC)/American Joint Committee on Cancer (AJCC) TNM staging system [1], primary breast cancers with extension to the skin are classified as T4. Patients with T4 carcinomas of any type, with or without lymph node involvement, and without distant metastases (T4 N0-2 M0), are classified as disease stage IIIB. According to this system, the breast carcinoma with skin involvement is included in stage III and may be considered as locally-advanced breast cancer (LABC) [1-3]. In addition to the tumour size and the (S)-crizotinib axillary lymph node involvement, other well-established prognostic factors Rabbit polyclonal to EGFR.EGFR is a receptor tyrosine kinase.Receptor for epidermal growth factor (EGF) and related growth factors including TGF-alpha, amphiregulin, betacellulin, heparin-binding EGF-like growth factor, GP30 and vaccinia virus growth factor. currently used in breast cancer include histological subtype or grade, estrogen (ER) and progesterone (PR) receptor status, em HER2 /em amplification, and Ki67 proliferation index [4,5]. Novel tumour markers with potential clinical utility are thus awaited. The molecular mechanisms underlying locally-advanced breast carcinomas are largely unknown. A distinct gene-expression profile has been described for T3/T4 tumours in comparison to the gene-expression pattern of T1/T2 tumours [6], suggesting that a distinct biological behaviour may characterize initial em vs /em . locally-advanced breast carcinomas. The mitogen activated protein kinase (MAPK) pathway, a major signalling cascade involved in the control of cell growth and proliferation, has been indicated to play a role in the intracellular signalling process of breast carcinomas [7-9]. The ERK1-2 proteins, which represent the final components of such a signalling kinase cascade, have been found (S)-crizotinib to be activated through phosphorilation (pERK1-2) in human cancer and implicated in rapid malignant cell growth, mostly as a consequence of mutations in upstream components of the pathway [10,11]. Presence of pERK1-2 could be thus considered as a marker for the increased activity of ERK1-2, which may induce cell proliferation, rapid cancer (S)-crizotinib cell growth, and resistance to apoptosis [10]. Moreover, a genomic instability with an increased number of copies of the em CyclinD1 /em gene, which encodes a component of the p16CDKN2A-RB pathway functionally interacting with the MAPK pathway [12,13], has been described to promote a deregulation of the cell cycle with subsequent induction of an uncontrolled cell proliferation and tumour growth [14]. Nevertheless, the p53 protein represent the final effector of the p14CDKN2A-MDM2 pathway; in majority of human cancers, the em TP53 /em gene is usually functionally inactivated [15]. Lack or reduced expression levels of the p53 protein seems to be associated with a defective apoptotic response to genotoxic damage and, thus, to anticancer brokers [16]. Finally, two additional mechanisms seem to play a central role in breast cancer progression and resistance to treatment. The increased expression of survivin, a member of the inhibitor-of-apoptosis (IAP) protein family, has been demonstrated to be associated with resistance to apoptosis [17-19]. It has been reported (S)-crizotinib that survivin and other IAP proteins cooperate to activate kinase cascades which control cell motility, thus stimulating.