Transient over-expression of estrogen receptor-α in breast cancer cells promotes cell survival and estrogen-independent growth

Robert S. Tolhurst (1) , Ross S. Thomas (1) , Fiona J. Kyle (1) , Hetal Patel (1) , Manikandan Periyasamy (1) , Andrew Photiou (1) , Paul T. R. Thiruchelvam (1) , Chun-Fui Lai (1) , Marwa Al-Sabbagh (1) , Rosemary A. Fisher (1) , Sayka Barry (2) , Tatjana Crnogorac-Jurcevic (2) , Lesley-Ann Martin (3) , Mitch Dowsett (3, 4) , R. Charles Coombes (1) , Tahereh Kamalati (1) , Simak Ali (1) , Laki Buluwela (1)

1 Division of Cancer, Department of Surgery & Cancer
2 Centre for Molecular Oncology & Imaging, Barts and The London School of Medicine and Dentistry
3 Breakthrough Breast Cancer Centre
4 The Royal Marsden Hospital

Estrogen receptor-α (ERα) positive breast cancer frequently responds to inhibitors of ERα activity, such as tamoxifen, and/or to aromatase inhibitors that block estrogen biosynthesis. However, many patients become resistant to these agents through mechanisms that remain unclear. Previous studies have shown that expression of ERα in ERα-negative breast cancer cell lines frequently inhibits their growth. In order to determine the consequence of ERα over-expression in ERα-positive breast cancer cells, we over-expressed ERα in the MCF-7 breast cancer cell line using adenovirus gene transduction. ERα over-expression led to ligand-independent expression of the estrogen-regulated genes pS2 and PR and growth in the absence of estrogen. Interestingly, prolonged culturing of these cells in estrogen-free conditions led to the outgrowth of cells capable of growth in cultures from ERα transduced, but not in control cultures. From these cultures a line, MLET5, was established which remained ERα-positive, but grew in an estrogen-independent manner. Moreover, MLET5 cells were inhibited by anti-estrogens showing that ERα remains important for their growth. Gene expression microarray analysis comparing MCF-7 cells with MLET5 highlighted apoptosis as a major functional grouping that is altered in MLET5 cells, such that cell survival would be favoured. This conclusion was further substantiated by the demonstration that MLET5 show resistance to etoposide-induced apoptosis. As the gene expression microarray analysis also shows that the apoptosis gene set differentially expressed in MLET5 is enriched for estrogen-regulated genes, our findings suggest that transient over-expression of ERα could lead to increased cell survival and the development of estrogen-independent growth, thereby contributing to resistance to endocrine therapies in breast cancer patients.

Mots clés: Estrogen; Estrogen withdrawal; Anti-estrogens; Estrogen receptor; Endocrine resistance; Gene profiling; Apoptosis

Robert S. Tolhurst, Ross S. Thomas, Fiona J. Kyle, Hetal Patel, Manikandan Periyasamy, et al.. Transient over-expression of estrogen receptor-α in breast cancer cells promotes cell survival and estrogen-independent growth. Breast Cancer Research and Treatment, 2010, 128 (2), pp.357-368. ⟨10.1007/s10549-010-1122-6⟩. ⟨hal-00615373⟩