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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Breast Neoplasms / metabolism*
  • Cell Proliferation / drug effects
  • Estrogens / chemistry*
  • Female
  • Gene Expression Profiling / methods*
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • MCF-7 Cells
  • Oligonucleotide Array Sequence Analysis
  • Receptors, Estrogen / metabolism
  • Selective Estrogen Receptor Modulators / therapeutic use
  • Sequence Analysis, RNA
  • Tamoxifen / analogs & derivatives
  • Tamoxifen / chemistry*


  • Estrogens
  • Receptors, Estrogen
  • Selective Estrogen Receptor Modulators
  • Tamoxifen
  • afimoxifene