Modulation of BAG-1 expression alters the sensitivity of breast cancer cells to tamoxifen.

Abstract

BACKGROUND:

BAG-1 (bcl-2 associated athanogene) is a multifunctional protein that protects cells from a wide range of apoptotic stimuli including radiation, hypoxia and chemotherapeutic agents. Overexpression of cytoplasmic BAG-1 has been associated with the increased survival and decreased response to treatment with tamoxifen (TAM) in breast cancer. We attempted to assess the expression of BAG-1 in the human breast cancer cells that are resistant to treatment with 4-OH TAM and effect of altered BAG-1 expression on their sensitivity to 4-OH TAM.

METHODS:

BAG-1 expression was examined in the MCF-7 cells that became resistant to 4-OH TAM. The 4-OH TAM-resistant MCF-7 cells were then transfected with the BAG-1 siRNA and the 4-OH TAM-sensitive MCF-7 cells with the plasmids carrying the human BAG-1 isoform-specific expression constructs respectively to investigate the effect of BAG-1 on the TAM-induced apoptosis.

RESULTS:

Our results showed that the TAM-resistant MCF-7 (TAMR/MCF-7) cells expressed higher level of BAG-1 than that of the MCF-7 cells. Down-regulation of BAG-1 significantly enhanced the sensitivity of the TAMR/MCF-7 cells to TAM treatment. Additionally, we found that BAG-1 p50 was the only isoform that inhibited the TAM-induced apoptosis in the MCF-7 cells, while the other isoforms had little effect.

CONCLUSION:

Our study indicated that up and down regulations of the BAG-1 expression were associated with the decreased and increased sensitivity to 4-OH TAM in the estrogen receptor-positive (ER+) human breast cancer cell line MCF-7 respectively, and distinct isoforms of BAG-1 had different anti-apoptotic ability in breast cancer cells treated with the 4-OH TAM.

• Authors: Hong Liu, Su Lu, Lin Gu, Yongchang Gao, Tong Wang, Jing Zhao, Jianyu Rao, Jun Chen, Xishan Hao, Shou-Ching Tang
• Journal: Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology (Cell Physiol Biochem) Vol. 33 Issue 2 Pg. 365-74 ( 2014) ISSN: 1421-9778 [Electronic] Germany
• PMID: 24557447 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 S. Karger AG, Basel.

Chemical References

• Antineoplastic Agents, Hormonal
• BCL2-associated athanogene 1 protein
• DNA-Binding Proteins
• Neoplasm Proteins
• Protein Isoforms
• Receptors, Estrogen
• Transcription Factors
• Tamoxifen

Topics

• Antineoplastic Agents, Hormonal (pharmacology)
• Apoptosis (drug effects, genetics)
• Breast Neoplasms (drug therapy, genetics, metabolism, pathology)
• Cell Line, Tumor
• DNA-Binding Proteins (biosynthesis, genetics)
• Down-Regulation (drug effects, genetics)
• Drug Resistance, Neoplasm (drug effects)
• Female
• Gene Expression Regulation, Neoplastic (drug effects, genetics)
• Humans
• Neoplasm Proteins (biosynthesis, genetics)
• Protein Isoforms (biosynthesis, genetics)
• Receptors, Estrogen (genetics, metabolism)
• Tamoxifen (pharmacology)
• Transcription Factors (biosynthesis, genetics)