Knockdown of the small conductance Ca(2+) -activated K(+) channels is potently cytotoxic in breast cancer cell lines.

BACKGROUND AND PURPOSE: Small conductance calcium-activated potassium (KCa 2.x) channels have a widely accepted canonical function in regulating cellular excitability. In this study, we address a potential non-canonical function of KCa 2.x channels in breast cancer cell survival, using in vitro models. EXPERIMENTAL APPROACH: The expression of all KCa 2.x channel isoforms was initially probed using RT-PCR, Western blotting and microarray analysis in five widely studied breast cancer cell lines. In order to assess the effect of pharmacological blockade and siRNA-mediated knockdown of KCa 2.x channels on these cell lines, we utilized MTS proliferation assays and also followed the corresponding expression of apoptotic markers. KEY RESULTS: All of the breast cancer cell lines, regardless of their lineage or endocrine responsiveness, were highly sensitive to KCa 2.x channel blockade. UCL1684 caused cytotoxicity, with LD50 values in the low nanomolar range, in all cell lines. The role of KCa 2.x channels was confirmed using pharmacological inhibition and siRNA-mediated knockdown. This reduced cell viability and also reduced expression of Bcl-2 but increased expression of active caspase-7 and caspase-9. Complementary to these results, a variety of cell lines can be protected from apoptosis induced by staurosporine using the KCa 2.x channel activator CyPPA. CONCLUSIONS AND IMPLICATIONS: In addition to a well-established role for KCa 2.x channels in migration, blockade of these channels was potently cytotoxic in breast cancer cell lines, pointing to modulation of KCa 2.x channels as a potential therapeutic approach to breast cancer.

Insulin-like growth factor-I receptor signaling and resistance in breast cancer.

Insulin-like growth factor-I receptor (IGF-IR) signaling is involved in many fundamental adverse aspects of cancer cell biology, such as proliferation, cell survival and migration. Its anti-apoptotic properties have implicated the receptor in mediating decreased sensitivity to chemotherapeutic drugs and radiation treatment; however, data are emerging that also indicates a role for IGF-IR signaling in resistance, not only to antihormones but also to antigrowth factor strategies such as agents that target the erb family of receptors. As such, IGF-IR is clearly an attractive therapeutic target for the treatment of cancer, including breast cancer, where there is evidence of clinical prominence of the IGF-IR pathway and, as such, numerous strategies are currently in development to inhibit IGF-IR signaling. This review focuses on the ability of the IGF-IR to contribute to resistance mechanisms that support breast cancer cell growth in the presence of antihormones and antigrowth factors and discusses methods to maximize antitumor effects by combination regimens cotargeting the IGF-IR that may delay, or even prevent, progression to the resistant phenotype.