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Eur J Cancer. 2014 Nov;50(16):2877-86. doi: 10.1016/j.ejca.2014.08.010. Epub 2014 Sep 15.

Identification of gene regulation patterns underlying both oestrogen- and tamoxifen-stimulated cell growth through global gene expression profiling in breast cancer cells.

Author information

1
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington DC 20057, United States.
2
Computational Biology Division, The Translational Genomics Research Institute, Phoenix, AZ 85004, United States.
3
Department of Medicine, Division of Oncology, The Genome Institute, Washington University, St. Louis, MO 63108, United States.
4
Biomedical Engineering Department, Oregon Health and Science University, Portland, OR 97239, United States.
5
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington DC 20057, United States. Electronic address: vcj2@georgetown.edu.

Abstract

PURPOSE:

A c-Src inhibitor blocks oestrogen (E2)-induced stress and converts E2 responses from inducing apoptosis to growth stimulation in E2-deprived breast cancer cells. A reprogrammed cell line, MCF-7:PF, results in a functional oestrogen receptor (ER). We addressed the question of whether the selective ER modulator 4-hydroxytamoxifen (4-OHT) could target ER to prevent E2-stimulated growth in MCF-7:PF cells.

METHODS:

Expression of mRNA was measured through real-time RT-PCR. Global gene expression profile was analysed through microarray. Transcriptome profiles were screened by RNA-sequencing.

RESULTS:

Unexpectedly, both 4-OHT and E2 stimulated cell growth in a concentration-dependent manner. Expression profiling showed a remarkable overlap in genes regulated in the same direction by E2 and 4-OHT. Pathway enrichment analysis of the 280 genes commonly deregulated in MCF-7:PF cells by 4-OHT and E2 revealed functions mainly related to membrane, cytoplasm and metabolic processes. Further analysis of 98 genes up-regulated by both 4-OHT and E2 uncovered a significant enrichment in genes associated with membrane remodelling, cytoskeleton reorganisation, cytoplasmic adapter proteins, cytoplasm organelle proteins and related processes. 4-OHT was more potent than E2 in up-regulating some membrane remodelling molecules, such as EHD2, FHL2, HOMER3 and RHOF. In contrast, 4-OHT acted as an antagonist to inhibit expression of the majority of enriched membrane-associated genes in wild-type MCF-7 cells.

CONCLUSIONS:

Long-term selection pressure has changed the cell population responses to 4-OHT. Membrane-associated signalling is critical for 4-OHT-stimulated cell growth in MCF-7:PF cells. This study provides a rationale for the further investigation of target therapy for tamoxifen resistant patients.

KEYWORDS:

Gene expression profiling; Membrane-associated molecules; Oestrogen; Tamoxifen

PMID:
25212499
PMCID:
PMC4210771
DOI:
10.1016/j.ejca.2014.08.010
[Indexed for MEDLINE]
Free PMC Article

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