Journal
MOLECULAR CANCER RESEARCH
Volume 16, Issue 4, Pages 720-727Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1541-7786.MCR-17-0480
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Funding
- grants for Breast Cancer Research Foundation
- Stand Up to Cancer
- National Foundation for Cancer Research
- Howard Hughes Medical Institute
- NIH [K12 5K12CA087723]
- NIBIB [EB008047]
- Susan G. Komen for the Cure [KG09042]
- ESSCO Breast Cancer Fund
- NCI Federal Share Program and Income
- MGH-Johnson & Johnson Center for Excellence in CTCs
- Human Frontiers Science Program
- Swiss National Science Foundation
- Swiss Foundation for Grants in Biology and Medicine
- [NIHCA129933]
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Molecular drivers underlying bone metastases in human cancer are not well understood, in part due to constraints in bone tissue sampling. Here, RNA sequencing was performed of circulating tumor cells (CTC) isolated from blood samples of women with metastatic estrogen receptor (ER) thorn breast cancer, comparing cases with progression in bone versus visceral organs. Among the activated cellular pathways in CTCs from bone-predominant breast cancer is androgen receptor (AR) signaling. AR gene expression is evident, as is its constitutively active splice variant AR-v7. AR expression within CTCs is correlated with the duration of treatment with aromatase inhibitors, suggesting that it contributes to acquired resistance to endocrine therapy. In an established breast cancer xenograft model, a bone-tropic derivative displays increased AR expression, whose genetic or pharmacologic suppression reduces metastases to bone but not to lungs. Together, these observations identify AR signaling in CTCs from women with bone-predominant ERthorn breast cancer, and provide a rationale for testing androgen inhibitors in this subset of patients. Implications: This study highlights a role for the AR in breast cancer bone metastasis, and suggests that therapeutic targeting of the AR may benefit patients with metastatic breast cancer. (C) 2018 AACR.
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