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Abstract
Fulvestrant is a representative pure antiestrogen and a Selective Estrogen Receptor Down-regulator (SERD). In contrast to the Selective Estrogen Receptor Modulators (SERMs) such as 4-hydroxytamoxifen that bind to estrogen receptor α (ERα) as antagonists or partial agonists, fulvestrant causes proteasomal degradation of ERα protein, shutting down the estrogen signaling to induce proliferation arrest and apoptosis of estrogen-dependent breast cancer cells. We performed genome-wide RNAi knockdown screenings for protein kinases required for fulvestrant-induced apoptosis of the MCF-7 estrogen-dependent human breast caner cells and identified the c-Src tyrosine kinase (CSK), a negative regulator of the oncoprotein c-Src and related protein tyrosine kinases, as one of the necessary molecules. Whereas RNAi knockdown of CSK in MCF-7 cells by shRNA-expressing lentiviruses strongly suppressed fulvestrant-induced cell death, CSK knockdown did not affect cytocidal actions of 4-hydroxytamoxifen or paclitaxel, a chemotherapeutic agent. In the absence of CSK, fulvestrant-induced proteasomal degradation of ERα protein was suppressed in both MCF-7 and T47D estrogen-dependent breast cancer cells whereas the TP53-mutated T47D cells were resistant to the cytocidal action of fulvestrant in the presence or absence of CSK. MCF-7 cell sensitivities to fulvestrant-induced cell death or ERα protein degradation was not affected by small-molecular-weight inhibitors of the tyrosine kinase activity of c-Src, suggesting possible involvement of other signaling molecules in CSK-dependent MCF-7 cell death induced by fulvestrant. Our observations suggest the importance of CSK in the determination of cellular sensitivity to the cytocidal action of fulvestrant.
Highlights
70% of breast cancers express estrogen receptor a (ERa), and most of these ERa-positive primary tumors depend on estrogen signaling for their growth and survival [1]
RNAi knockdown of c-Src tyrosine kinase (CSK) did not affect the tamoxifen effect at all. These results indicate that CSK is required for fulvestrant (SERD)induced MCF-7 cell death while it is dispensable for the cytocidal action of tamoxifen (SERM)
Chu et al reported that the E2-triggered proteasomal degradation of ERa protein in MCF-7 cells were enhanced by activation of c-Src [81]
Summary
70% of breast cancers express estrogen receptor a (ERa), and most of these ERa-positive primary tumors depend on estrogen signaling for their growth and survival [1]. ERa interacts with other signaling kinases and adaptor molecules such as c-Src [20], Shc [21], PAK1 [22], DLC1 [23,24], PELP1/MNAR [22,25,26], and p85 PI3-kinase regulatory subunit [27] These interactions lead to activation of downstream signaling kinases such as the p42/44 MAPK and AKT [28], which play critical roles in regulating cell proliferation and survival. Taking a similar approach of Iorns et al, in the present study we performed lentivirus-based RNAi knockdown screening experiments covering the entire human kinases and phosphatases and identified CSK (cSrc tyrosine kinase) as a novel signaling molecule required for fulvestrant-induced MCF-7 cell death. We provide evidence that this strong specificity of fulvestrant resistance caused by CSK knockdown was due to suppression of the fulvestrant-induced proteasomal degradation of ERa protein, which is not involved in the mechanisms of actions of tamoxifen or paclitaxel. Our present study provides important insights into the molecular mechanisms of the cytocidal action of fulvestrant in human breast cancer cells, providing evidence of requirement of CSK
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