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another widely-held assumption bites the dust: tamoxifen works vs ER- bc cells
(at least in the lab)
: Mol Cell Biochem. 2007 Jul 24; [Epub ahead of print]
Regulation of intracellular calcium release and PP1alpha in a mechanism for 4-hydroxytamoxifen-induced cytotoxicity.
Bollig A, Xu L, Thakur A, Wu J, Kuo TH, Liao JD.
Karmanos Cancer Institute, Wayne State University, 110 E Warren, HWCRC room 731, Detroit, MI, 48201, USA.
Treatment with tamoxifen, or its metabolite 4-hydroxytamoxifen (4OHT), has cytostatic and cytotoxic effects on breast cancer cells in vivo and in culture. Although the effectiveness of 4OHT as an anti-breast cancer agent is due to its action as an estrogen receptor-alpha (ERalpha) antagonist, evidences show that 4OHT is also cytotoxic for ERalpha-negative breast cancer cells and can be effective therapy against tumors that lack estrogen receptors. These findings underscore 4OHT signaling complexities and belie the most basic understandings of 4OHT action and resistance. Here, we have investigated the effects of 4OHT on Ca(2+) homeostasis and cell death in breast cancer cells in culture. Measurement of Ca(2+) signaling in breast cancer cells showed that 4OHT treatment altered Ca(2+) homeostasis and was cytotoxic for both an ERalpha+ and an ERalpha- cell line, MCF-7 and MDA-MB-231, respectively. Further investigation lead us to the novel discovery that 4OHT-induced increase of ATP-dependent Ca(2+) release from the endoplasmic reticulum correlated with 4OHT-induced upregulation of protein phosphatase 1alpha (PP1alpha) and the inositol 1,4,5-trisphosphate receptor (IP3R). Blocking 4OHT-induced PP1alpha upregulation by siRNA strategy reduced the effects of 4OHT on both Ca(2+) signaling and cytotoxicity. Results from these investigations strongly suggest a role for PP1alpha upregulation in a mechanism for 4OHT-induced changes to Ca(2+) signaling that ultimately contribute to the cytotoxic effects of 4OHT.
PMID: 17646931 [PubMed - as supplied by publisher]
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