00085472can112073-sup-figure_2_pdf_154k.pdf (154.13 kB)
Supplementary Figure 2 from Metastatic Progression with Resistance to Aromatase Inhibitors Is Driven by the Steroid Receptor Coactivator SRC-1
journal contributionposted on 2023-03-30, 21:05 authored by Jean McBryan, Sarah M. Theissen, Christopher Byrne, Eamon Hughes, Sinead Cocchiglia, Stephen Sande, Jane O'Hara, Paul Tibbitts, Arnold D.K. Hill, Leonie S. Young
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ARTICLE ABSTRACTAromatase inhibitors (AI) are a standard-of-care treatment for postmenopausal, estrogen receptor–positive breast cancers. Although tumor recurrence on AI therapy occurs, the mechanisms underlying acquired resistance to AIs remain unknown. In this study, we examined a cohort of endocrine-treated breast cancer patients and used a cell line model of resistance to the AI letrozole. In patients treated with a first-line AI, hormone receptor switching between primary and resistant tumors was a common feature of disease recurrence. Resistant cells exhibited a switch from steroid-responsive growth to growth factor–responsive and endocrine-independent growth, which was accompanied by the development of a more migratory and disorganized phenotype. Both the resistant cells and tumors from AI-resistant patients showed high expression of the steroid receptor coactivator SRC-1. Direct interactions between SRC-1 and the transcription factor Ets2 regulated Myc and MMP9. SRC-1 was required for the aggressive and motile phenotype of AI-resistant cells. Interestingly, SRC-1 expression in primary and/or recurrent tumors was associated with a reduction in disease-free survival in treated patients. Moreover, there was a significant association between SRC-1 and Ets2 in the recurrent tissue compared with the matched primary tumor. Together, our findings elucidate a mechanism of AI-specific metastatic progression in which interactions between SRC-1 and Ets2 promote dedifferentiation and migration in hormone-dependent breast cancer. Cancer Res; 72(2); 548–59. ©2011 AACR.
BiomarkersMetastasis biomarkersBreast CancerCancer InterceptionBiomarkers and interventionCancer PreventionEarly DetectionCarcinogenesisSignal transductionDrug ResistanceRegulation of gene expression in drug resistanceEndocrinologySteroid hormones and receptorsProgression, Invasion & MetastasisMigration and invasion