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

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 brea...

Full description

Saved in:
Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2012-01, Vol.72 (2), p.548-559
Main Authors: MCBRYAN, Jean, THEISSEN, Sarah M, BYRNE, Christopher, HUGHES, Eamon, COCCHIGLIA, Sinead, SANDE, Stephen, O'HARA, Jane, TIBBITTS, Paul, HILL, Arnold D. K, YOUNG, Leonie S
Format: Article
Language:English
Subjects:
Antineoplastic agents
Aromatase Inhibitors - pharmacology
Biological and medical sciences
Breast Neoplasms - drug therapy
Breast Neoplasms - metabolism
Cell Line, Tumor
Disease Progression
Female
Humans
Medical sciences
Neoplasm Metastasis
Nuclear Receptor Coactivator 1 - metabolism
Pharmacology. Drug treatments
Tamoxifen - pharmacology
Transfection
Tumors
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-11-2073