HIPK2 may undergo to some mutations,

and another intriguing mechanism of HIPK2 inhibition is the reported LOH in well differentiated thyroid carcinomas and in mice. Moreover, the just discovered role of HIPK2 selleck products in cytokinesis implies its control on chromosomal instability which AZD7762 concentration allows tumorigenesis. Therefore, these findings, by demonstrating the contributions of HIPK2 signaling to tumor regression and response to therapies, propose HIPK2 as potential diagnostic marker and a therapeutic target. What does the future hold for this promising tumor suppressor protein? Other than unveiling novel roles for HIPK2 in anticancer mechanisms, one intriguing area will be to discover selective compounds for HIPK2 (re)activation, for anticancer therapeutic purpose. High Content Screening Ethical approval Any experimental research that is reported in the manuscript have been performed, reviewed, and approved by the appropriate ethics committee of the Regina Elena National Cancer Institute, Rome, Italy. Research carried out on humans was in compliance with the Helsinki Declaration, and the experimental research on animals followed internationally recognized guidelines. Acknowledgements The research work in D’Orazi, Rinaldo and Soddu laboratories is supported by grants from the Italian Association for Cancer Research (AIRC), Ministero della Salute “Progetto Giovani Ricercatori,” MFAG-10363), and Fondo Investimenti

della Ricerca di Base. We thank Dr. M Mottolese for the breast ductal carcinoma immunostaining. We apologize to all our colleagues whose work could not be cited in this article due to space limitations. References 1. Hanahan D, Weinberg RA: Hallmarks of cancer: the next generation.

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As shown in Figure 1C and 1D, the pretreatment of E2 for 16 hours or 12 days significantly increased the cell death induced by chemotherapeutic agents, such as paclitaxel, fluorouracil, and vinorelbine (p < 0.05). Moreover, fulvestrant reversed the enhancing effect of E2 on the chemotherapeutic agents-induced cell death (p < 0.05). Treatment of ERα-positive T47D cells with E2 up-regulated the expression of the bcl-2 protein The experimental

results in this work showed that ERα mediated chemosensitivity in T47D cells. However, some reports have shown that ERα mediated chemoresitance in breast cancer cells through the regulation of Bcl-2 family [2, 10, 11, 13, 14]. ERα-positive breast cancer cells usually express Bcl-2, whereas ERα-negative HDAC inhibitors list ones express little or no Bcl-2 JAK inhibitor [22, 23]. We investigated the expressions of Bcl-2 and Bax in T47D cells after incubation with E2 and/or fulvestrant for 12 days in order to determine whether Bcl-2 family contributed to ERα-mediated chemosensitivity. As shown in Figure 2, the treatment of T47D cells with E2 for 12 days resulted in a marked increase in Bcl-2 expression, and fulvestrant reversed the upregulation of Bcl-2. Bax protein was undetectable in T47D cells grown in an E2-free medium or in a medium supplemented with 100 nM E2 for 12 days.

Considering the antiapoptotic function of Bcl-2, these results suggested that ERα-mediated chemosensitivity in T47D cells was not due to Bcl-2 alteration induced by E2. Figure 2 Effects of E2 on Bcl-2 and Bax expression in T47D cells. Treatment of ERα-positive T47D cells with

E2 for 12 days upregulated the expression of Bcl-2 protein. Fulvestrant inhibited its expression. Bax failed to be detected by western blot in T47D cells. Treatment with E2 enhanced the growth of T47D cells, whereas fulvestrant inhibited its growth The cell cycle plays a critical role in chemosensitivity, particularly for cycle-specific chemotherapeutic Urocanase agents. High levels of cell proliferation Q-VD-Oph concentration normally lead to increased sensitivity to chemotherapeutic agents. Since apoptosis-related protein Bcl-2 and Bax do not contribute to ERα-mediated chemosensitivity in T47D cells, we investigated the role of cell cycle alteration in this process. The results presented in Figure 3A and 3B show that E2 treatment for 16 hours decreased the percentage of T47D cells in G1 phase, as compared with the cells grown in the absence of E2, with a concomitant increase in S and G2/M phase population. E2 treatment for 12 days led to greater accumulation of cells in the S and G2/M phases. E2 induced an increase in the proliferative potential of T47D cells, which was demonstrated by the growth curve. In addition, E2 promoted T47D cell growth significantly compared with the control cell group. Fulvestrant completely inhibited E2-induced cell proliferation.