The role of the glucocorticoid receptor in anti-hormone resistance in breast cancer

Abstract

Background: Approximately 75% of all breast cancer diagnoses are oestrogen receptor a (ERa) positive. In such ERa positive subtypes, anti-hormones such as fulvestrant and tamoxifen are a mainstay therapy. However, the efficacy of these agents is severely limited by subsequent development of resistance. The glucocorticoid receptor (GR) has been implicated as a possible resistance mechanism owing to transcription of pro-proliferative and anti-apoptotic genes in breast cancer cells. A similar contributory role to resistance has also been observed in anti-hormone resistant prostate cancer suggested by increased GR expression and tumour progression. These associations are of particular concern given the use of glucocorticoids as an adjuvant treatment in breast cancer. This research aims to assess the impact of fulvestrant and tamoxifen on GR expression in the anti-hormone treated and resistant MCF-7 ERa positive breast cancer cell line. Methods: mRNA and protein expression of the GR were investigated by reverse transcription polymerase chain reaction and Western blotting respectively, in the ERa-positive MCF-7 breast cancer cell line. Expression in wild-type cells was compared to cells following short-term (7 day) oestrogen (1nM) and fulvestrant (100nM) treatment, and in cells with acquired resistance to fulvestrant and tamoxifen. Results:  Both fulvestrant -treated and -resistant MCF-7 cells exhibited increased GR mRNA and protein expression which was statistically significant in resistant cells at the protein (p=0.0345) but not mRNA level. Tamoxifen-resistant cells also exhibited increased GR protein expression. Conclusions: These data demonstrate up-regulation of the GR during treatment with, and following acquisition of resistance to, the anti-hormone fulvestrant. This supports potential for increased expression of GR-regulated pro-survival genes in resistance, indicating a potential role for the GR in anti-hormone resistant breast cancer. Further research into this area is warranted to improve clinical outcomes.