SHON Is a Novel Estrogen-Regulated Oncogene in Mammary Carcinoma That Predicts Patient Response to Endocrine Therapy

Jung, Yewon; Abdel-Fatah, Tarek M.; Chan, Sy; Nolan, Christopher C.; Green, Andrew; Ellis, Ian O.; Li, Lili; Huang, Baiqu; Lü, Jun; Xu, Bing; Chen, Longxin; Runlin, Z.; Zhang, Min; Wang, Jingru; Wu, Zhengsheng; Zhu, Tao; Perry, Jo K.; Lobie, Peter E.; Liu, Dong-Xu

doi:10.1158/0008-5472.can-13-0982

Cited by 5 publications

(25 citation statements)

References 46 publications

(38 reference statements)

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“…We previously showed that SHON was able to oncogenically transform the immortalized normal human mammary epithelial cell line MCF10A . To determine whether SHON is involved in EMT, we first stably overexpressed SHON in MCF10A cell line, and the expression was confirmed by immunoblotting (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The details of the SHON ‐expressing plasmid pIRESneo3‐SHON and the pIRESneo3 empty vector, the SHON ‐specific siRNA‐expressing plasmid pSilencer 2.1‐U6‐shSHON (shSHON) and the negative siRNA control pSilencer 2.1‐U6 (shCtrl) were previously described . The constructions of the SHON‐flag fusion expression plasmid and the stable cell lines are detailed in Supporting Information for Materials and Methods.…”

Section: Methodsmentioning

confidence: 99%

“…We have recently identified a novel secreted hominoid oncogene, termed SHON , in breast cancer, and found that it plays an important role in the development of mammary carcinoma . SHON is expressed in most human cancer cell lines, and is oncogenic for human mammary carcinoma cells.…”

mentioning

confidence: 99%

“…SHON is expressed in most human cancer cell lines, and is oncogenic for human mammary carcinoma cells. SHON expression is correlated with tumor grades and can be used as a prognostic biomarker to predict a patient's response to endocrine therapy in breast cancer . SHON has also been shown to upregulate many important regulators of EMT, such as Snail , Vimentin and Twist .…”

mentioning

confidence: 99%

“…SHON expression is correlated with tumor grades and can be used as a prognostic biomarker to predict a patient's response to endocrine therapy in breast cancer . SHON has also been shown to upregulate many important regulators of EMT, such as Snail , Vimentin and Twist . On the basis of these previous data, we speculate that SHON might play a role in breast cancer progression through induction of an oncogenic EMT program.…”

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SHON, a novel secreted protein, regulates epithelial–mesenchymal transition through transforming growth factor‐β signaling in human breast cancer cells

Liu

Zhang

et al. 2014

Intl Journal of Cancer

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The epithelial-mesenchymal transition (EMT) is one of the main mechanisms contributing to the onset of cancer metastasis, and has proven to be associated with breast cancer progression. SHON is a novel secreted hominoid-specific protein we have previously identified; it is specifically expressed in all human cancer cell lines tested and is oncogenic for human mammary carcinoma cells. Here, we show that ectopic overexpression of SHON in immortalized human mammary epithelial cells is sufficient for cells to acquire the mesenchymal traits, as well as the enhanced cell migration and invasion, along with the epithelial stem cell properties characterized by increased CD44 high /CD24 low subpopulation and mammosphere-forming ability. Moreover, we demonstrate that SHON positively activates the autocrine transforming growth factor-b (TGF-b) pathway to contribute to EMT, while SHON itself is induced by TGF-b in mammary epithelial cells. These data are in favor of a SHON-TGFb-SHON-positive feedback loop that regulates EMT program in breast cancer progression. Finally, examination of the human clinic breast cancer specimens reveals that tumor cells may extracellularly release SHON protein to promote the cancerization of surrounding cells. Together, our findings define an important function of SHON in regulation of EMT via TGF-b signaling, which is closely associated with the invasive subtypes of human breast cancer.Breast cancer remains the most commonly diagnosed cancer among women both in developed and developing countries. 1 Tumor metastasis is the leading cause of mortality associated with cancer including breast cancer. 2-4 The epithelial-mesenchymal transition (EMT), a developmental process in which epithelial cells lose their polarity and acquire the migratory properties of mesenchymal cells, is known to be the pivotal mechanism contributing to cancer metastasis. EMT is characterized by the dissolution of cell-cell junctions, cytoskeletal rearrangements, increased cell motility and synthesis of extracellular matrix. [4][5][6] In addition, certain epithelial cells that undergo an EMT acquire stem-like properties. 7,8 In association with these properties, many EMT biomarkers have been identified, some of which have been used to detect EMT in clinical samples. 9,10 Although the phenotypic correlation between EMT and cancer progression is firmly established, the underlying molecular mechanisms remain largely unclear.The transforming growth factor-b (TGF-b) has emerged as a potent inducer of EMT, and it induces EMT in cultured cells, allowing for dissection of signaling pathways that lead to Moreover, increased production of active TGFb by tumor cells, which enhances the autocrine signaling of TGF-b, is thought to contribute to EMT in carcinoma cells in vivo. [16][17][18]

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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SHON, a novel secreted protein, regulates epithelial–mesenchymal transition through transforming growth factor‐β signaling in human breast cancer cells

Liu

Zhang

et al. 2014

Intl Journal of Cancer

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SHON expression predicts response and relapse risk of breast cancer patients after anthracycline-based combination chemotherapy or tamoxifen treatment

et al. 2019

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BACKGROUND: SHON nuclear expression (SHON-Nuc +) was previously reported to predict clinical outcomes to tamoxifen therapy in ERα + breast cancer (BC). Herein we determined if SHON expression detected by specific monoclonal antibodies could provide a more accurate prediction and serve as a biomarker for anthracycline-based combination chemotherapy (ACT). METHODS: SHON expression was determined by immunohistochemistry in the Nottingham early-stage-BC cohort (n = 1,650) who, if eligible, received adjuvant tamoxifen; the Nottingham ERα − early-stage-BC (n = 697) patients who received adjuvant ACT; and the Nottingham locally advanced-BC cohort who received pre-operative ACT with/without taxanes (Neo-ACT, n = 120) and if eligible, 5-year adjuvant tamoxifen treatment. Prognostic significance of SHON and its relationship with the clinical outcome of treatments were analysed. RESULTS: As previously reported, SHON-Nuc + in high risk/ERα + patients was significantly associated with a 48% death risk reduction after exclusive adjuvant tamoxifen treatment compared with SHON-Nuc − [HR (95% CI) = 0.52 (0.34-0.78), p = 0.002]. Meanwhile, in ERα − patients treated with adjuvant ACT, SHON cytoplasmic expression (SHON-Cyto +) was significantly associated with a 50% death risk reduction compared with SHON-Cyto − [HR (95% CI) = 0.50 (0.34-0.73), p = 0.0003]. Moreover, in patients received Neo-ACT, SHON-Nuc − or SHON-Cyto + was associated with an increased pathological complete response (pCR) compared with SHON-Nuc + [21 vs 4%; OR (95% CI) = 5.88 (1.28-27.03), p = 0.012], or SHON-Cyto − [20.5 vs. 4.5%; OR (95% CI) = 5.43 (1.18-25.03), p = 0.017], respectively. After receiving Neo-ACT, patients with SHON-Nuc + had a significantly lower distant relapse risk compared to those with SHON-Nuc − [HR (95% CI) = 0.41 (0.19-0.87), p = 0.038], whereas SHON-Cyto + patients had a significantly higher distant relapse risk compared to SHON-Cyto − patients [HR (95% CI) = 4.63 (1.05-20.39), p = 0.043]. Furthermore, multivariate Cox regression analyses revealed that SHON-Cyto + was independently associated with a higher risk of distant relapse after Neo-ACT and 5-year tamoxifen treatment [HR (95% CI) = 5.08 (1.13-44.52), p = 0.037]. The interaction term between ERα status and SHON-Nuc + (p = 0.005), and between SHON-Nuc + and tamoxifen therapy (p = 0.007), were both statistically significant. CONCLUSION: SHON-Nuce + in tumours predicts response to tamoxifen in ERα + BC while SHON-Cyto + predicts response to ACT.

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Big-data-based edge biomarkers: study on dynamical drug sensitivity and resistance in individuals

Zeng¹,

Zhang²,

Yu³

et al. 2015

Brief Bioinform

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Big-data-based edge biomarker is a new concept to characterize disease features based on biomedical big data in a dynamical and network manner, which also provides alternative strategies to indicate disease status in single samples. This article gives a comprehensive review on big-data-based edge biomarkers for complex diseases in an individual patient, which are defined as biomarkers based on network information and high-dimensional data. Specifically, we firstly introduce the sources and structures of biomedical big data accessible in public for edge biomarker and disease study. We show that biomedical big data are typically 'small-sample size in high-dimension space', i.e. small samples but with high dimensions on features (e.g. omics data) for each individual, in contrast to traditional big data in many other fields characterized as 'large-sample size in low-dimension space', i.e. big samples but with low dimensions on features. Then, we demonstrate the concept, model and algorithm for edge biomarkers and further big-data-based edge biomarkers. Dissimilar to conventional biomarkers, edge biomarkers, e.g. module biomarkers in module network rewiring-analysis, are able to predict the disease state by learning differential associations between molecules rather than differential expressions of molecules during disease progression or treatment in individual patients. In particular, in contrast to using the information of the common molecules or edges (i.e.molecule-pairs) across a population in traditional biomarkers including network and edge biomarkers, big-data-based edge biomarkers are specific for each individual and thus can accurately evaluate the disease state by considering the individual heterogeneity. Therefore, the measurement of big data in a high-dimensional space is required not only in the learning process but also in the diagnosing or predicting process of the tested individual. Finally, we provide a case study on analyzing the temporal expression data from a malaria vaccine trial by big-data-based edge biomarkers from module network rewiring-analysis. The illustrative results show that the identified module biomarkers can accurately distinguish vaccines with or without protection and outperformed previous reported gene signatures in terms of effectiveness and efficiency.

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SHON Is a Novel Estrogen-Regulated Oncogene in Mammary Carcinoma That Predicts Patient Response to Endocrine Therapy

Abstract: Endocrine therapies are the primary systemic intervention for patients with estrogen receptor-positive (ER þ ) breast cancer.

Cited by 5 publications

References 46 publications

SHON, a novel secreted protein, regulates epithelial–mesenchymal transition through transforming growth factor‐β signaling in human breast cancer cells

SHON, a novel secreted protein, regulates epithelial–mesenchymal transition through transforming growth factor‐β signaling in human breast cancer cells

SHON expression predicts response and relapse risk of breast cancer patients after anthracycline-based combination chemotherapy or tamoxifen treatment

Big-data-based edge biomarkers: study on dynamical drug sensitivity and resistance in individuals

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