Metastatic Progression with Resistance to Aromatase Inhibitors Is Driven by the Steroid Receptor Coactivator SRC-1

Jean McBryan,Paul Tibbitts,Stephen Sande,Christopher Byrne,Leonie S. Young,Arnold D.K. Hill,Sinead Cocchiglia,Sarah M. Theissen,Jane O'Hara,Eamon Hughes

doi:10.1158/0008-5472.can-11-2073

Jean McBryan, Paul Tibbitts + Show 8 more

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https://doi.org/10.1158/0008-5472.can-11-2073

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Abstract

Aromatase 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.

Highlights

Endocrine therapies, including estrogen receptor (ER) modulators and aromatase inhibitors (AI), are first-line treatment for ER-positive breast cancer
Endocrine resistance is thought to involve, at least in part, a switch from steroid signaling to growth factor signaling, leading to a steroid-independent tumor [18]. In keeping with this hypothesis, we identified a significant association between lack of progesterone receptor (PR) expression in the primary tumor and reduced early response to AI treatments (Fig. 1A, P 1⁄4 0.02 at 2-year follow-up; Supplementary Fig. S1A)
The development of resistance to AI therapy is marked by a shift in cancer cell status from steroid dependent to steroid independent/growth factor dependent

Summary

Introduction

Endocrine therapies, including estrogen receptor (ER) modulators and aromatase inhibitors (AI), are first-line treatment for ER-positive breast cancer. AIs, do not remove all of the estrogen ligand—data from molecular and in vivo studies suggest that this can result in adaptive hypersensitivity of the intact ER via increased signaling through growth factor pathways [3]. The significance of this hypersensitivity and Authors' Affiliation: Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons in Ireland, Dublin, Ireland. Alterations in steroid receptor profile observed in clinical studies between primary and metastatic breast cancer, in particular with loss of progesterone receptor (PR) status, support the phenomenon of tumor adaptability in endocrine-resistant patients [4]. Conversion from serum Her negative to positive has been reported as an independent risk factor for decreased survival in both tamoxifen and AItreated patients [5]

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