Abstract
Endocrine therapies are the primary systemic intervention for patients with estrogen receptor-positive (ER(+)) breast cancer. However, a significant proportion of initially responsive ER(+) tumors develop resistance, with relapses occurring in up to 50% of patients. Lack of reliable predictive biomarkers remains an unfilled need for enhanced clinical management of this disease. In this study, we address this need in identifying a novel estrogen-regulated gene called SHON (secreted hominoid-specific oncogene). Enforced expression of SHON in breast cancer cells increased their proliferation, survival, migration, and invasion in vitro. Furthermore, SHON enhanced the oncogenicity of these cells in xenograft models of human breast cancer and was also sufficient to oncogenically transform MCF10A human mammary epithelial cells. Conversely, SHON attenuation mediated by RNA interference- or antibody-based methods reduced the oncogenicity of breast cancer cells. Mechanistic investigations indicated that the oncogenic transforming properties of SHON were mediated by BCL-2 and NF-κB. In primary clinical specimens, SHON was immunohistochemically detected in 62% of breast cancers, in which its expression was positively correlated with ER expression. In this setting, SHON expression predicted a favorable response to endocrine therapy in high-risk patients with ER(+) breast cancer. Taken together, our findings identify SHON as a novel human oncogene with predictive utility in ER(+) breast cancer, perhaps offering a simple biomarker to predict the therapeutic efficacy of antiestrogen therapy in patients with breast cancer.
Highlights
Breast cancer is the most prevalent cancer in females worldwide
Sequence homology searches using National Center for Biotechnology Information (NCBI) basic local alignment search tool (BLAST) revealed that SHON belongs to a hominoid-specific gene family with no known orthologs outside the primate lineage
Our results presented here have demonstrated that SHON is a novel hominoid-specific gene that enhances oncogenicity of mammary carcinoma cell lines
Summary
Breast cancer is the most prevalent cancer in females worldwide. Estrogen signaling and estrogen receptors (ER) play a pivotal role in the initiation and progression of breastAuthors' Affiliations: 1Liggins Institute, University of Auckland, Auckland, New Zealand; 2Department of Clinical Oncology; 3Department of Histopathology, School of Molecular Medical Sciences, University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom; 4The Key Laboratory of Molecular Epigenetics of Ministry of Education, Northeast Normal University; 5The Institute of Genetics and Cytology, Northeast Normal University, Changchun; 6Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing; 7Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China; 8Department of Pathology, Anhui Medical University, Hefei, China; 9Cancer Science Institute of Singapore, and Department of Pharmacology, National University of Singapore; and 10National Cancer Institute of Singapore, National University Health System, SingaporeNote: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).Ó2013 American Association for Cancer Research.cancer, with the majority of human breast cancer being initially estrogen dependent. Breast cancer is the most prevalent cancer in females worldwide. Estrogen signaling and estrogen receptors (ER) play a pivotal role in the initiation and progression of breast. Cancer, with the majority of human breast cancer being initially estrogen dependent. In accepted models of ER function, estrogen binding to either ERa or ERb results in dimerization and conformational change [1]. The resulting estrogen–ER complex modulates gene transcription by binding to estrogen response elements in DNA, or by interaction with other transcription factors such as specificity protein 1 (SP1), activating protein 1 (AP-1), or NF-kB [2]. Expression arrays have identified early and late estrogen responsive genes [5], including genes involved in cancer cell proliferation and survival, enhancing our understanding of the molecular events involved in estrogen action
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