Fiona J Kyle

Publications (2)8.86 Total impact

• Source

  Available from: cnrs.fr

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

  Robert S Tolhurst, Ross S Thomas, Fiona J Kyle, Hetal Patel, Manikandan Periyasamy, Andrew Photiou, Paul T R Thiruchelvam, Chun-Fui Lai, Marwa Al-Sabbagh, Rosemary A Fisher, Sayka Barry, Tatjana Crnogorac-Jurcevic, Lesley-Ann Martin, Mitch Dowsett, R Charles Coombes, Tahereh Kamalati, Simak Ali, Laki Buluwela
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  ABSTRACT: 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.
  Breast Cancer Research and Treatment 07/2011; 128(2):357-68. · 4.43 Impact Factor
• Source

  Available from: Eric Ortlund

  Article: The liver receptor homolog-1 regulates estrogen receptor expression in breast cancer cells.

  Paul T R Thiruchelvam, Chun-Fui Lai, Hui Hua, Ross S Thomas, Antoni Hurtado, William Hudson, Andrew R Bayly, Fiona J Kyle, Manikandan Periyasamy, Andrew Photiou, Alan C Spivey, Eric A Ortlund, Richard J Whitby, Jason S Carroll, R Charles Coombes, Laki Buluwela, Simak Ali
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  ABSTRACT: Estrogen receptor-α (ER) is expressed in the great majority of breast cancers, and the inhibition of ER action is a key part of breast cancer treatment. The inhibition of ER action is achieved using anti-estrogens, primarily tamoxifen, and with aromatase inhibitors that inhibit estrogen biosynthesis, thereby preventing ER activation. However, resistance to these therapies is common. With the aim of identifying new molecular targets for breast cancer therapy, we have identified the liver receptor homolog-1 (LRH-1) as an estrogen-regulated gene. RNA interference and over-expression studies were used to investigate the role of the LRH-1 in regulating breast cancer growth and to identify the targets of an LRH-1 action. Promoter recruitment was determined using reporter gene and chromatin immunoprecipitation (ChIP) assays. We show that LRH-1 regulates breast cancer cell growth by regulating the ER expression. Reporter gene and in vitro DNA-binding assays identified an LRH-1-binding site in the ER gene promoter, and ChIP assays have demonstrated in vivo binding at this site. We also provide evidence for new LRH-1 variants in breast cancer cells arising from the use of alternative promoters. Previous studies have shown that LRH-1 functions in estrogen biosynthesis by regulating aromatase expression. Our findings extend this by highlighting LRH-1 as a key regulator of the estrogen response in breast cancer cells through the regulation of ER expression. Hence, inhibition of LRH-1 could provide a powerful new approach for the treatment of endocrine-resistant breast cancer.
  Breast Cancer Research and Treatment 06/2011; 127(2):385-96. · 4.43 Impact Factor