Abstract
IntroductionAdjuvant treatment with tamoxifen substantially improves survival of women with estrogen-receptor positive (ER+) tumors. Tamoxifen resistance (TAMR) limits clinical benefit. RRR-α-tocopherol ether-linked acetic acid analogue (α-TEA) is a small bioactive lipid with potent anticancer activity. We evaluated the ability of α-TEA in the presence of tamoxifen to circumvent TAMR in human breast cancer cell lines.MethodsTwo genotypically matched sets of TAM-sensitive (TAMS) and TAM-resistant (TAMR) human breast cancer cell lines were assessed for signal-transduction events with Western blotting, apoptosis induction with Annexin V-FITC/PI assays, and characterization of cholesterol-rich microdomains with fluorescence staining. Critical involvement of selected mediators was determined by using RNA interference and chemical inhibitors.ResultsGrowth-factor receptors (total and phosphorylated forms of HER-1 and HER-2), their downstream prosurvival mediators pAkt, pmTOR, and pERK1/2, phosphorylated form of estrogen receptor-α (pER-α at Ser-167 and Ser-118, and cholesterol-rich lipid microdomains were highly amplified in TAMR cell lines and enhanced by treatment with TAM. α-TEA disrupted cholesterol-rich microdomains, acted cooperatively with TAM to reduce prosurvival mediators, and induced DR5-mediated mitochondria-dependent apoptosis via an endoplasmic reticulum stress-triggered pro-death pJNK/CHOP/DR5 amplification loop. Furthermore, methyl-β-cyclodextrin (MβCD), a chemical disruptor of cholesterol rich microdomains, acted cooperatively with TAM to reduce prosurvival mediators and to induce apoptosis.ConclusionsData for the first time document that targeting cholesterol-rich lipid microdomains is a potential strategy to circumvent TAMR, and the combination of α-TEA + TAM can circumvent TAMR by suppression of prosurvival signaling via disruption of cholesterol-rich lipid microdomains and activation of apoptotic pathways via induction of endoplasmic reticulum stress.
Highlights
Adjuvant treatment with tamoxifen substantially improves survival of women with estrogen-receptor positive (ER+) tumors
Growth-factor receptors, their downstream prosurvival mediators pAkt, phosphorylated mammalian target of rapamycin (pmTOR), and phosphorylated-extracellular signalregulated kinases 1 and 2 (pERK1/2), phosphorylated form of estrogen receptor-a
Data for the first time document that targeting cholesterol-rich lipid microdomains is a potential strategy to circumvent Tamoxifen resistance (TAMR), and the combination of a-TEA + TAM can circumvent TAMR by suppression of prosurvival signaling via disruption of cholesterol-rich lipid microdomains and activation of apoptotic pathways via induction of endoplasmic reticulum stress
Summary
Adjuvant treatment with tamoxifen substantially improves survival of women with estrogen-receptor positive (ER+) tumors. We evaluated the ability of a-TEA in the presence of tamoxifen to circumvent TAMR in human breast cancer cell lines. TAM, which binds to ER-a and antagonizes ER-a actions in breast tissue, has been the mainstay of endocrine therapy in both early and advanced ER+ breast cancer patients for almost three decades. De novo and acquired resistance may occur through altered cell-signaling mediators, leading to estrogen-independent activation of ERmediated gene expression and hormone independence [4]. TAMR cells have been shown to overexpress receptor tyrosine kinases (RTKs), such as HER-1 and HER-2, and to crosstalk with membraneassociated ER (mER), leading to nuclear estrogen-receptor (nER) dependent and independent cell proliferation in which TAM acts as an agonist [6,7,8]
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