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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.

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



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.


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.


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.


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.


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

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