Abstract
IntroductionTamoxifen is the most widely prescribed anti-estrogen treatment for patients with estrogen receptor (ER)-positive breast cancer. However, there is still a need for biomarkers that reliably predict endocrine sensitivity in breast cancers and these may well be expressed in a dynamic manner.MethodsIn this study we assessed gene expression changes at multiple time points (days 1, 2, 4, 7, 14) after tamoxifen treatment in the ER-positive ZR-75-1 xenograft model that displays significant changes in apoptosis, proliferation and angiogenesis within 2 days of therapy.ResultsHierarchical clustering identified six time-related gene expression patterns, which separated into three groups: two with early/transient responses, two with continuous/late responses and two with variable response patterns. The early/transient response represented reductions in many genes that are involved in cell cycle and proliferation (e.g. BUB1B, CCNA2, CDKN3, MKI67, UBE2C), whereas the continuous/late changed genes represented the more classical estrogen response genes (e.g. TFF1, TFF3, IGFBP5). Genes and the proteins they encode were confirmed to have similar temporal patterns of expression in vitro and in vivo and correlated with reduction in tumour volume in primary breast cancer. The profiles of genes that were most differentially expressed on days 2, 4 and 7 following treatment were able to predict prognosis, whereas those most changed on days 1 and 14 were not, in four tamoxifen treated datasets representing a total of 404 patients.ConclusionsBoth early/transient/proliferation response genes and continuous/late/estrogen-response genes are able to predict prognosis of primary breast tumours in a dynamic manner. Temporal expression of therapy-response genes is clearly an important factor in characterising the response to endocrine therapy in breast tumours which has significant implications for the timing of biopsies in neoadjuvant biomarker studies.
Highlights
Tamoxifen is the most widely prescribed anti-estrogen treatment for patients with estrogen receptor (ER)-positive breast cancer
Dynamic changes in gene expression produced by tamoxifen The effect of tamoxifen on tumor volume growth and gene expression were studied on days 1, 2, 4, 7 and 14 after initiation of tamoxifen treatment and compared with tumors grown in the absence of tamoxifen
There was good agreement between the expression levels of xenograft replicates at most time points and the pattern of expression of these genes over the five time points was most consistently separated into six sets using hierarchical clustering (Figure 1b)
Summary
Tamoxifen is the most widely prescribed anti-estrogen treatment for patients with estrogen receptor (ER)-positive breast cancer. Tamoxifen is still the most widely prescribed anti-estrogen for patients with ER-positive breast cancer and has improved survival in women initially receiving this drug as adjuvant therapy [2]. Previous attempts to characterize the gene expression response to tamoxifen in breast tumors in vivo have been limited to single time points [8,9]. A recent time course experiment demonstrated dynamic gene expression changes in response to estradiol (E2) in ZR-751 cell lines in vitro [10]. Xenograft models allow assessment of dynamic changes in tissue gene expression at multiple time points from tissue, which is not feasible in the clinical setting. An in vivo model allows the effect of stromal elements and matrix elements to contribute to expression, which cannot be reproduced in vitro
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