AR Expression in Breast Cancer CTCs Associates with Bone Metastases.

Abstract

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)+ 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 ER+ 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. Mol Cancer Res; 16(4); 720-7. ©2018 AACR.

• Authors: Nicola Aceto, Aditya Bardia, Ben S Wittner, Maria C Donaldson, Ryan O'Keefe, Amanda Engstrom, Francesca Bersani, Yu Zheng, Valentine Comaills, Kira Niederhoffer, Huili Zhu, Olivia Mackenzie, Toshi Shioda, Dennis Sgroi, Ravi Kapur, David T Ting, Beverly Moy, Sridhar Ramaswamy, Mehmet Toner, Daniel A Haber, Shyamala Maheswaran
• Journal: Molecular cancer research : MCR (Mol Cancer Res) Vol. 16 Issue 4 Pg. 720-727 (04 2018) ISSN: 1557-3125 [Electronic] United States
• PMID: 29453314 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• AR protein, human
• Antineoplastic Agents, Hormonal
• Biomarkers, Tumor
• Receptors, Androgen

Topics

• Abdominal Neoplasms (secondary)
• Alternative Splicing
• Animals
• Antineoplastic Agents, Hormonal (therapeutic use)
• Biomarkers, Tumor (genetics)
• Bone Neoplasms (drug therapy, genetics, secondary)
• Breast Neoplasms (drug therapy, genetics)
• Drug Resistance, Neoplasm
• Female
• Humans
• Mice
• Neoplastic Cells, Circulating (chemistry)
• Receptors, Androgen (genetics)
• Sequence Analysis, RNA
• Single-Cell Analysis