Feng Qian, Email: nc.
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Chao Cheng, Phone: , Email: ude. National Center for Biotechnology Information , U. BMC Cancer. Published online May 2. Mark , 1 Frederick S. Varn , 1 Matthew H. Ung , 1 Feng Qian , 2 and Chao Cheng 1, 3, 4. Author information Article notes Copyright and License information Disclaimer. Corresponding author.
Received Mar 15; Accepted Apr This article has been cited by other articles in PMC. Abstract Background Neoadjuvant chemotherapy is a key component of breast cancer treatment regimens and pathologic complete response to this therapy varies among patients. Methods We applied our previously developed E2F4 genomic signature to predict neoadjuvant chemotherapy response in breast cancer. Results In all datasets, E2F4 activity level was an accurate predictor of neoadjuvant chemotherapy response, with high E2F4 scores predictive of achieving pathologic complete response and low scores predictive of residual disease.
Conclusion Overall, we show that our E2F4 signature is accurate in predicting patient response to neoadjuvant chemotherapy. Electronic supplementary material The online version of this article doi Background Neoadjuvant chemotherapy is a well-established treatment regimen used in managing patients with early-stage breast cancer [ 1 ].
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Calculation of the E2F4 signature The gene binary E2F4 target gene signature was determined as described previously [ 17 ]. Survival analyses A univariate Cox proportional hazards model was used to measure the association between patient E2F4 activity and survival outcome, while Kaplan-Meier curves were generated to visualize the survival distributions for all binary comparisons.
Open in a separate window. Comparison of the E2F4 signature with other clinically-available prognostic assays By using the E2F4 signature, we achieved good accuracy in classifying samples into pCR and RD. Validation of the E2F4 signature in other datasets To validate our results found from the Hatzis dataset, we applied our E2F4 signature to predict neoadjuvant response in four independent datasets by Iwamoto et al. A modified E2F4 signature composed of 33 genes is highly predictive of chemotherapy response. Discussion E2F4 is an essential cell cycle regulator that has been broadly implicated in tumorigenesis and cancer severity [ 29 — 31 ].
Conclusion In conclusion, we have demonstrated that a target gene-based signature of the transcription factor E2F4 can be used to predict response to neoadjuvant chemotherapy. Acknowledgements We thank E. Competing interests The authors declare that they have no competing interests. Consent for publication Not applicable. Ethics approval and consent to participate Not applicable. Additional file Additional file 1: K, pdf Clinical characteristics by dataset of samples used in analysis.
Contributor Information Kenneth M. References 1. Neoadjuvant therapy for breast cancer. J Surg Oncol. Management of stage III primary breast cancer with primary chemotherapy, surgery, and radiation therapy. Induction chemotherapy followed by breast conservation for locally advanced carcinoma of the breast.
Defining the benefits of neoadjuvant chemotherapy for breast cancer. J Clin Oncol. Clinical course of breast cancer patients with complete pathologic primary tumor and axillary lymph node response to doxorubicin-based neoadjuvant chemotherapy. Preoperative chemotherapy in primary operable breast cancer: results from the European Organization for Research and Treatment of cancer trial JAMA Surg.
Clinical and radiologic assessments to predict breast cancer pathologic complete response to neoadjuvant chemotherapy. Breast Cancer Res Treat. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med. Gene expression profiling predicts clinical outcome of breast cancer. A gene-expression signature as a predictor of survival in breast cancer. Evaluating the gene assay recurrence score R as a predictor of clinical response to 24 weeks of neoadjuvant exemestane in estrogen receptor-positive breast cancer. Int J Clin Oncol. Gene expression patterns in formalin-fixed, paraffin-embedded core biopsies predict docetaxel chemosensitivity in breast cancer patients.
The predictive value of the gene signature for adjuvant chemotherapy in early breast cancer. A diagnostic gene profile for molecular subtyping of breast cancer associated with treatment response. E2F4 regulatory program predicts patient survival prognosis in breast cancer. Breast Cancer Res. The E2F4 prognostic signature is also predictive of the pathological response of breast cancer to chemotherapy.
Cancer Genome Atlas N Comprehensive molecular portraits of human breast tumours. Inferring activity changes of transcription factors by binding association with sorted expression profiles. BMC bioinformatics.
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REACTIN: regulatory activity inference of transcription factors underlying human diseases with application to breast cancer. BMC Genomics. A three-gene model to robustly identify breast cancer molecular subtypes. J Natl Cancer Inst. Gene-expression profiles to predict distant metastasis of lymph-node-negative primary breast cancer. An introduction to statistical learning: with applications in R. In: Springer texts in statistics. New York: Springer-Verlag; A genomic predictor of response and survival following taxane-anthracycline chemotherapy for invasive breast cancer.
Gene pathways associated with prognosis and chemotherapy sensitivity in molecular subtypes of breast cancer. Evaluation of a gene paclitaxel, fluorouracil, doxorubicin, and cyclophosphamide chemotherapy response predictor in a multicenter randomized trial in breast cancer. Clin Cancer Res. Frequent mutation of the E2F-4 cell cycle gene in primary human gastrointestinal tumors. Cancer Res.
Schwemmle S, Pfeifer GP. Therefore, to uncover the underlying molecular mechanism driving this process might contribute to the perfection of new metastatic paradigms and the development of future therapeutic interventions for metastasis. Cullin1 CUL1 is the first and most extensively characterized member of the cullin family.
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Thus, CUL1 regulates specific ubiquitination of some proteins and then mediates diverse cellular processes, including early embryonic development and cell cycle control 5 , 6. Our previous studies have indicated that CUL1 is aberrantly upregulated and significantly correlated with lymphatic and distant metastasis in different types of cancers, such as colorectal cancer 7 , hepatocellular cancer 8 , gastric cancer 9 , and renal cancer cancer Recently, we have shown that the positive CUL1 staining in cancer tissues predicts poor prognosis of breast cancer patients, and subsequent cancer cell research shows that silencing of CUL1 in cancer cells inhibited the cell migration and invasion abilities through downregulating MMP-2 and MMP-9 expressions In this study, we conducted a series of in vitro and in vivo experiments and the gene expression profiling to further perfect molecular mechanism of CUL1 in breast cancer metastasis.
As shown in Fig. Usually, the acquisition of stronger migration and invasion capabilities and the change of fibroblast-like morphology of MCF10A cells were associated with epithelial to mesenchymal transition EMT , so we examined the epithelial and mesenchymal markers. Our results showed that the CUL1 overexpressed MCF10A cells exhibited a dramatically downregulation of E-cadherin; meanwhile the mesenchymal markers N-cadherin, vimentin, and fibronectin were dramatically upregulated Fig.
Since tumor metastasis involves sequential multi-steps, including migration, invasion, angiogenesis, and so on 4 , here we firstly performed the transwell and tube formation assays in vitro. The tube formation assay showed that the conditioned medium from CUL1 knockdown cells significantly decreased the number of complete tubule structures formed by HUVEC cells Fig.
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Next, we sought to determine whether CUL1 could promote metastasis and angiogenesis in vivo. After 1 month, bioluminescence imaging was used to monitor the metastatic lesions. Our results exhibited that lung was the main target organ for breast cancer metastasis and the fluc activity in the CUL1 knockdown group is much lower than the control one Fig. Using the subcutaneous matrigel plug assays, we demonstrated that the reduced vascularization in matrigel plugs containing MDA-MB cells with CUL1 knockdown when compared with the control plugs Fig.
Accordingly, the immunohistochemical staining demonstrated that CUL1 expression was significantly downregulated in the knockdown group Fig. To further elucidate the mechanism by which CUL1 regulates the breast cancer migration, invasion, metastasis, and angiogenesis, we conducted gene expression profiling of CUL1 knockdown and vector control MDA-MB cells in triplicate Fig.
The heat map and volcano plot showed that CUL1 knockdown affected genes upregulated and downregulated Fig. The classification of disease and function was conducted to enrich the differential genes. As cytokines play important roles in tumor migration, invasion, and angiogenesis, the reduction of cytokines was of particular interest CUL1 expression was divided into high and low groups based on the average value. Moreover, cell migration and tube formation assays also showed that EZH2 overexpression rescued CUL1 knockdown-reduced cell migration Fig.
Our previous study has indicated that CUL1 is positively associated with poor 5-year overall and disease-specific survival of breast cancer patients Most of breast cancer-related deaths are due to metastasis diseases. Since tumor metastasis involves sequential multi-steps, including angiogenesis, migration, invasion, and so on 4 , in our study, we designed a series of experiments to explore the roles of CUL1 in breast cancer metastasis.
Our data showed that CUL1 was highly expressed in breast cancer cells when compared with normal mammary epithelial cells. Overexpression of CUL1 in normal mammary epithelial cells significantly increased the cell migration and invasion and showed the elongated fibroblast-like morphology through inducing EMT, while knockdown of CUL1 inhibited breast cancer cell migration, invasion, and tube formation in vitro. Using intravenous tumor metastasis model and angiogenesis in vivo, we indicated that CUL1 knockdown significantly reduced the lung metastasis and angiogenesis.
Together, these results showed that CUL1 played as an important regulator of breast cancer metastasis. With regard to the potential of CUL1 in breast cancer migration, invasion, angiogenesis, and metastasis, we further investigated the molecular mechanism on the functional properties. In the study, microarray analysis was used to determine global transcriptional changes in cell lines and revealed that hundreds of genes were regulated by CUL1 knockdown. The analyses of disease and function network showed cytokines were significantly enriched in the migration function of cancer cells.
It is well known that autocrine cytokines regulate divergent tumor cell behaviors and tumor microenvironment Autocrine cytokines CXCL8 and IL11 induce neo-angiogenesis through activation of the vascular endothelial growth factor pathway. Additionally, they enhance the activity of MMP-2 and MMP-9 which in turn increase the metastatic activity of the underlying malignancy 17 , 18 , 19 , These data are accorded with our previous researches in breast cancer and renal cell carcinoma that CUL1 increases cancer cell metastasis through upregulating the activity of MMP-2 and MMP-9 refs.
Though here CUL1 knockdown did not significantly reduced the expression of CXCL8, other researches have indicated that critical inflammatory genes, especially the coordination of autocrine expressions of the pro-inflammatory cytokines IL6 and CXCL8, play important roles in the growth of triple-negative breast cancer cells Having seen cytokines changes resulted from the CUL1 knockdown, here we went on elucidating the signaling pathways how CUL1 regulated these two cytokines. Using the Z -score arithmetic, several transcriptional factors were predicted to be activated and inhibited, and subsequent protein results reminded us that EZH2 might play as the most important common transcriptional regulator.
EZH2 is known as the catalytic subunit of the polycomb repressive complex 2, which is a highly conserved histone methyltransferase that methylates lysine 27 of histone 3 ref. Studies have indicated that EZH2 can act as a gene silencer or a transcriptional gene activator. These findings suggested that CUL1 could stimulate the production of cytokines through inducing EZH2 expression to regulate breast cancer metastasis.
In this study, we elucidated this signaling pathway on CUL1-regulated breast cancer metastasis. Combined with our previous report about CUL1, we proposed that CUL1 may serve as a promising therapeutic target for breast cancer metastasis. MCF10A cells were cultured as previously described Western blotting was carried out as previously reported Each blot was repeated three times. Primer sequences are listed below. The migration and invasion assays were performed as described before Then, 1. No Expire eBook. Amazon Marketplace Used. Amazon Marketplace New.
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