Targeting cholesterol-rich microdomains to circumvent tamoxifen-resistant breast cancer.

Abstract

INTRODUCTION:

Adjuvant 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.

METHODS:

Two 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.

RESULTS:

Growth-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.

CONCLUSIONS:

Data 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.

• Authors: Richa Tiwary, Weiping Yu, Linda A deGraffenried, Bob G Sanders, Kimberly Kline
• Journal: Breast cancer research : BCR (Breast Cancer Res) Vol. 13 Issue 6 Pg. R120 ( 2011) ISSN: 1465-542X [Electronic] England
• PMID: 22115051 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Hormonal
• Antioxidants
• beta-Cyclodextrins
• methyl-beta-cyclodextrin
• Tamoxifen
• Cholesterol
• alpha-Tocopherol

Topics

• Antineoplastic Agents, Hormonal (pharmacology, therapeutic use)
• Antioxidants (pharmacology)
• Apoptosis (drug effects)
• Breast Neoplasms (drug therapy, metabolism)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Cholesterol (metabolism)
• Drug Resistance, Neoplasm
• Female
• Humans
• Membrane Microdomains (drug effects, metabolism)
• Signal Transduction (drug effects)
• Tamoxifen (pharmacology, therapeutic use)
• alpha-Tocopherol (pharmacology)
• beta-Cyclodextrins (pharmacology)