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J Cancer 2017; 8(6):1045-1052. doi:10.7150/jca.13690 This issue Cite

Research Paper

Bone metastasis-related signaling pathways in breast cancers stratified by estrogen receptor status

Naoki Hayashi¹, Takayuki Iwamoto¹, Yuan Qi², Naoki Niikura¹, Libero Santarpia^{1, 5}, Hideko Yamauchi³, Seigo Nakamura⁴, Gabriel N. Hortobagyi¹, Lajos Pusztai¹, W. Fraser Symmans⁵, Naoto T. Ueno^1✉

1. Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA;
2. Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA;
3. Department of Breast Surgical Oncology, St. Luke's International Hospital, Tokyo, Japan;
4. Department of Surgery, Division of Breast Surgical Oncology, Showa University School of Medicine, Tokyo, Japan;
5. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

✉ Corresponding author: Naoto T. Ueno, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1354, Houston, TX 77030; Tel: (713) 792-8754; Fax: (713) 794-4385; E-mail: nuenoorg. More

Abstract

Background: Breast cancer bone metastasis (BCBM)-specific genes have been reported without considering biological differences based on estrogen receptor (ER) status. The aims of this study were to identify BCBM-specific genes using our patient dataset and validate previously reported BCBM-specific genes, and to determine whether ER-status-related biological differences matter in identification of BCBM-specific genes.

Methods: We used Affymetrix GeneChips to analyze 365 primary human epidermal growth factor receptor 2 (HER2)-negative invasive breast cancer specimens. Genes that were differentially expressed between patients who developed bone metastasis and those who developed non-bone metastasis were identified using Cox proportional hazards model, and differential expression of gene sets was assessed using gene set analysis. We performed gene set analysis to determine whether biological function associated with bone metastasis were different by ER status using 2,246 functionally annotated gene sets assembled from Gene Ontology data base.

Results: Among 16,712 probe sets, 592 were overexpressed in the bone metastasis cohort compared to the non-bone-metastasis cohort (false discovery rate ≤ 0.05). However, no BCBM-specific genes met our significance tests when the cancers were stratified by ER status. In ER-positive and ER-negative breast cancers, 151 and 125 gene sets, respectively, were overexpressed for BCBM and the majority of BCBM-related pathways were different. Of significant gene sets, only 13 gene sets were overlapped between ER-positive and -negative cohorts.

Conclusion: ER-positive and ER-negative breast cancers have different biological pathways in BCBM development. We have yet to explore BCBM-related biomarkers and targets considering the biological features associated with BCBM depending on the ER status.

Keywords: Breast cancer, bone metastasis, gene expression, gene sets, estrogen receptor status.

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