Abstract
BackgroundEstrogen is a pivotal regulator of cell proliferation in the normal breast and breast cancer. Endocrine therapies targeting the estrogen receptor are effective in breast cancer, but their success is limited by intrinsic and acquired resistance.Methodology/Principal FindingsWith the goal of gaining mechanistic insights into estrogen action and endocrine resistance, we classified estrogen-regulated genes by function, and determined the relationship between functionally-related genesets and the response to tamoxifen in breast cancer patients. Estrogen-responsive genes were identified by transcript profiling of MCF-7 breast cancer cells. Pathway analysis based on functional annotation of these estrogen-regulated genes identified gene signatures with known or predicted roles in cell cycle control, cell growth (i.e. ribosome biogenesis and protein synthesis), cell death/survival signaling and transcriptional regulation. Since inducible expression of c-Myc in antiestrogen-arrested cells can recapitulate many of the effects of estrogen on molecular endpoints related to cell cycle progression, the estrogen-regulated genes that were also targets of c-Myc were identified using cells inducibly expressing c-Myc. Selected genes classified as estrogen and c-Myc targets displayed similar levels of regulation by estrogen and c-Myc and were not estrogen-regulated in the presence of siMyc. Genes regulated by c-Myc accounted for 50% of all acutely estrogen-regulated genes but comprised 85% (110/129 genes) in the cell growth signature. siRNA-mediated inhibition of c-Myc induction impaired estrogen regulation of ribosome biogenesis and protein synthesis, consistent with the prediction that estrogen regulates cell growth principally via c-Myc. The ‘cell cycle’, ‘cell growth’ and ‘cell death’ gene signatures each identified patients with an attenuated response in a cohort of 246 tamoxifen-treated patients. In multivariate analysis the cell death signature was predictive independent of the cell cycle and cell growth signatures.Conclusions/SignificanceThese functionally-based gene signatures can stratify patients treated with tamoxifen into groups with differing outcome, and potentially identify distinct mechanisms of tamoxifen resistance.
Highlights
Among several advances that have contributed to the decreased mortality from breast cancer observed in the past decade, the routine use of adjuvant endocrine therapies directed at the estrogen-estrogen receptor (ER) pathway is a major contributor [1,2]
Since inducible expression of c-Myc can overcome the inhibitory effects of antiestrogens and recapitulate many of the effects of estrogen on molecular endpoints related to cell cycle progression [13] we reasoned that determining which estrogenregulated genes were targets of c-Myc might provide insights into the role of c-Myc in different aspects of estrogen action and in antiestrogen resistance
Relationship between functional signatures and response to endocrine therapy To determine whether the individual processes regulated by estrogen might have different impacts on the response to endocrine therapy, we examined the relationship between the estrogen-regulated gene signatures and breast cancer patient outcome using transcript profiles generated from a population of 246 women with ER-positive breast cancer who received tamoxifen as their only adjuvant systemic therapy [11]
Summary
Among several advances that have contributed to the decreased mortality from breast cancer observed in the past decade, the routine use of adjuvant endocrine therapies directed at the estrogen-estrogen receptor (ER) pathway is a major contributor [1,2]. Targeting the estrogen receptor pathway is a validated, effective, biologically-based therapy for breast cancer. Prospective identification of patients who are not good candidates for adjuvant endocrine therapy would substantially facilitate clinical decision-making. To address this need, several gene expression signatures that cosegregate with poor outcome in tamoxifen-treated breast cancer have been derived using gene expression profiling, prospectively-selected candidate genes or differentially-expressed estrogen-regulated genes [reviewed in 10]. There is little overlap between the genes contained within these signatures, other than the frequent inclusion of genes involved in cell proliferation, and potentially clinically useful, they offer limited insight into the molecular basis of endocrine resistance. Endocrine therapies targeting the estrogen receptor are effective in breast cancer, but their success is limited by intrinsic and acquired resistance
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