|Year : 2018 | Volume
| Issue : 4 | Page : 297-304
EPOR mRNA level: A valuable prognostic indicator for patients with ER+ breast cancer
Jing Pan1, Xing-Hua Han2, Wei Wang2, Yue-Yin Pan2
1 Department of Medical Oncology, Anhui Provincial Hospital, Anhui Medical University, Hefei 230001, P.R. China
2 Department of Medical Oncology, Anhui Provincial Hospital, Anhui Medical University; Department of Medical Oncology, The First Affiliated Hospital of University of Science and Technology of China, Hefei 230001, P.R. China
|Date of Submission||20-Jan-2018|
|Date of Decision||23-Feb-2018|
|Date of Acceptance||20-Mar-2018|
|Date of Web Publication||30-Apr-2018|
Department of Medical Oncology, The First Affiliated Hospital of University of Science and Technology of China, No.17 Lujiang Road, Luyang District, Hefei 230001
Source of Support: None, Conflict of Interest: None
Objective: To explore the expression level and prognostic significance of erythropoietin receptor (EPOR) in patients with breast cancer (BRCA) based on estrogen receptor (ER) status and different molecular subtypes. Methods: The Cancer Genome Atlas (TCGA) and GTEx data were collected in GEPIA initially to identify the dysregulated genes. Further, bc- GenExMiner 4.1 online bioinformatics tool was used to evaluate EPOR mRNA differential expression level according to different classification of clinicopathologic parameters in patients with breast cancer. Additionally, the prognostic value between EPOR mRNA expression and free survival of metastatic relapse (MR) or any event (AE, namely any relapse or death) in patients with breast cancer was done. Results: EPOR mRNA was significantly downregulated in BRCA (1 085 cases) compared to normal tissues (291 cases) (P<0.05). Univariate Cox analysis revealed that high EPOR mRNA expression was remarkably correlated to a decreased risk of MR (HR: 0.79, P<0.000 1) and AE (HR: 0.87, P =0.000 7) especially in breast cancer patients with ER+. Besides, high EPOR mRNA level also associated with a favorable MR- free survival (HR: 0.81, P =0.007 2) and AE-free survival (HR: 0.88, P =0.029 9) in ER+ breast cancer patients. However, no similar above phenomenon was detected in ER- patients. Moreover, the subsequent prognostic adjusted analyses and univariate Cox analysis of AE based on SSP or SCM molecular subtypes validated the above results. Conclusion: EPOR mRNA level is a valuable prognostic indicator for patients with ER+ breast cancer.
Keywords: Breast cancer, EPOR, Prognosis, Bioinformatics
|How to cite this article:|
Pan J, Han XH, Wang W, Pan YY. EPOR mRNA level: A valuable prognostic indicator for patients with ER+ breast cancer. Asian Pac J Trop Med 2018;11:297-304
|How to cite this URL:|
Pan J, Han XH, Wang W, Pan YY. EPOR mRNA level: A valuable prognostic indicator for patients with ER+ breast cancer. Asian Pac J Trop Med [serial online] 2018 [cited 2019 May 24];11:297-304. Available from: http://www.apjtm.org/text.asp?2018/11/4/297/231471
Foundation project: This work was done in the Department of Medical Oncology, The First Affiliated Hospital of University of Science and Technology of China.
| 1. Introduction|| |
Breast cancer (BRCA) is one of the leading causes of cancer death among women worldwide and the number of newly diagnosed is gradually increasing in recent years,. To further acquire early detection and improve the treatment effect of advanced breast cancer, a great deal of efforts has been made. But unfortunately, the mortality of breast cancer patients is still maintaining higher and becoming a globally difficult question,. Recently, accumulating studies have demonstrated that exploration and validation of newly biomarkers or prognostic factors could improve clinical outcomes of breast cancer patients to some extent.
Erythropoietin receptor (EPOR) is a transmembrane protein of 484 amino acids and a calculated mass of 52.6 kDa, which increases to about 60 kDa due to glycosylation and phosphorylation. Recently, many studies focus their attention on this gene mainly due to the clinical use of recombinant human erythropoietin (rHuEPO) in cancer patients. In 2003, two large randomized controlled trials highlighting unexpected and deleterious effects of therapeutically- administered rHuEPO were published,. Starting from this, many controversies and conflicting conclusions have been gradually discovered. Some studies have found that rHuEPO can stimulate the EPOR expression level through activating JAK2-STAT5 or PI3K- AKT signal pathway and high EPOR expression will induce tumor growth and metastasis in many kinds of malignances ,,,. On the contrary, other studies have revealed that there is no influence of rHuEPO use on the EPOR expression, and even these corresponding authors have detected the low expression level or no expression of EPOR in malignancies ,,,,. They pointed out the potential reason may be partly associated with non-specificity of the antibodies used for detection of EPOR protein,. As for breast cancer, a similar paradoxical phenomenon exists as the above. Therefore, it is rather necessary to explore the expression of EPOR in breast cancer from the aspect of mRNA and whether it has a prognostic value.
Thus, in the present study, The Cancer Genome Atlas More Details (TCGA) and GTEx data were collected in GEPIA initially to identify the dysregulated gene EPOR. Further, bc-GenExMiner 4.1 online bioinformatics tool was used to evaluate EPOR mRNA differential expression level according to different classification of clinicopathologic parameters in patients with breast cancer. Additionally, the prognostic value between EPOR mRNA level and free survival of metastatic relapse (MR) or any event (AE, namely any relapse or death) in patients with breast cancer was investigated.
| 2. Materials and methods|| |
2.1. Mining of dysregulated EPOR gene in breast cancer
GEPIA (Website: http://gepia.cancer-pku.cn/) is a newly developed interactive web server for analyzing the RNA sequencing expression data of 9 736 tumors and 8 587 normal samples from the TCGA and the GTEx projects, using a standard processing pipeline. Initially, to explore whether EPOR mRNA levels have the significance of differential expression between breast cancer and normal tissues, GEPIA was used to draw the “Expression on Box Plots” under the selection of “Breast Cancer (BRCA) Datasets”. Besides, differential expression levels of EPOR mRNA in BRCA patients were analyzed by bc-GenExMiner v4.1 (breast cancer Gene-Expression Miner v4.1, website: http://bcgenex.centregauducheau.fr/BC-GEM/GEM- Accueil.php?js=1), a large free and open source database containing information about 5 861 cases of BRCA patients,, based on different kinds of classified parameters: Receptor statuses (ER+ vs. ER-, PR+ vs. PR-, HER2+ vs. HER2-), Nodal status (N+ vs. N-), SBR (SBR1 vs. SBR2 vs. SBR3), NPI (NPI1 vs. NPI2 vs. NPI3), Age (≤40/40-70/≥70 and ≤51/>51), Molecular subtypes, Basal-like (PAM50) and/or TNBC.
2.2. Correlation between EPOR mRNA expression levels and survival of breast cancer patients by bioinformatic analysis
To explore the correlation between EPOR mRNA level and the risk of MR or AE, MR-free and AE-free survival in BRCA patients, meta-analysis was done further through using bc-GenExMiner 4.1. Besides, subgroup analysis was done based on ER status, or molecular subtypes, or two types of molecular subtype predictors (SSP and SCM), respectively. The prognostic significance of EPOR mRNA level in BRCA patients was assessed by using univariate Cox regression model and drawing Kaplan-Meier curve and forest plot. Additionally, NPI-, AOL- and proliferation- adjusted analyses were further performed to verify the independent prognostic significance of EPOR mRNA in breast cancer.
| 3. Results|| |
3.1. EPOR mRNA was downregulated in BRCA compared to normal tissues
Through searching the TCGA and GTEx data in GEPIA, we found that EPOR mRNA was dramatically downregulated in BRCA (1 085 cases) compared to normal tissues (291 cases) (P <0.05, [Figure 1]A. Then, in order to further know whether or not significantly differential expression levels of EPOR mRNA existed in breast cancer patients based on different kinds of classified parameters, bc- GenExMiner v4.1 was employed. The results showed that there were remarkably differential expression levels of EPOR mRNA in ER+ vs. ER- patients (ER+ > ER-, [Figure 1]B, PR+ vs. PR- patients (PR+ > PR-, [Figure 1]C, NPI1 vs. NPI2 vs. NPI3patients (NPI1 > NPI2 > NPI3), SBR1 vs. SBR2 vs. SBR3patients (SBR1 > SBR2 > SBR3), Basal-like vs. Not basal-like patients (Not basal-like >Basal-like, [Figure 1]H, Basal-like and TNBC vs. Not basal-like and not TNBC patients (Not basal-like and not TNBC >Basal-like and TNBC, [Figure 1]I, TNBC vs. Not TNBC patients (Not TNBC >TNBC, [Figure 1]J, respectively. While, no significant expression difference of EPOR mRNA was found in HER2+ vs. HER2- patients [Figure 1]D or N+ vs. N- patients [Figure 1]E.
|Figure 1: Differential expression levels of EPOR mRNA in breast cancer patients based on different kinds of classified parameters.|
(A) TCGA data revealed that EPOR mRNA was significantly lower in breast cancer tissues (1 085 cases) than that in normal tissues (291 cases); (B-J) differential expression levels of EPOR mRNA in breast cancer patients were performed by bc-GenExMiner v4.1 based on different kinds of classified parameters: ER+ vs. ER- (B), PR+ vs. PR- (C), HER2+ vs. HER2- (D), N+ vs. N- (E), NPI1 vs. NPI2 vs. NPI3 (F), SBR1 vs. SBR2 vs. SBR3 (G), Basal-like vs. Not basal-like (H), Basal-like and TNBC vs. Not basal-like and not TNBC (I), TNBC vs. Not TNBC (J).
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3.2. High expression of EPOR mRNA was dramatically related to decreased risk of MR and AE in ERm or ER+ breast cancer patients
By exploring in bc-GenExMiner 4.1, totally 33 studies including 5 064 patients investigated the correlation between EPOR mRNA level and MR or AE [Table 1]. Initially, a preliminary study was done to investigate the prognostic analysis for EPOR mRNA expression with any ER status, any nodal status and any event. As shown in [Table 2], high EPOR mRNA expression was closely related to the decreased risk of MR and AE in ERm or ER+ patients. Nevertheless, the same relationship was not detected in ER- patients [Table 2]. These results suggested that EPOR mRNA level might have diverse prognostic significance in different subtypes of breast cancer.
|Table 2: Exhaustive EPOR univariate Coxanalysis of MR and AE in breast cancer patients.|
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3.3. EPOR univariate Cox regression analysis and adjusted analyses of MR based on ER status
To explore whether EPOR mRNA level had diverse prognostic significance in ER+ or ER- breast cancer patients, subgroup analysis was done further. As shown in [Figure 2]A, a total of 23 studies including 2 822 patients were searched to evaluate the correlation between EPOR mRNA level and MR risk in ER+ BRCA patients. The univariate Cox regression analysis demonstrated that high EPOR mRNA level was dramatically related to a lower risk of MR (HR: 0.79, P<0.000 1; [Figure 2]A and also a better MR-free survival (HR: 0.81, 95%CI: 0.70-0.94, P =0.007 2; [Figure 2]B. Besides, NPI-, AOL- and proliferation- adjusted analyses validated that high EPOR mRNA level was significantly correlated to a lower risk of MR in ER+ patients (HR: 0.81, 0.66 and 0.76, respectively; P =0.017 4, 0.000 9 and <0.000 1, respectively; [Figure 2]C. As for ER- patients, a total of 21 studies including 1 073 patients were searched to evaluate the relationship between EPOR mRNA level and MR risk [Figure 2]D. The results revealed no significant correlation no matter in univariate Cox regression analysis [Figure 2]E or in NPI-, AOL- and proliferation- adjusted analysis [Figure 2]F.
|Figure 2: EPOR univariate Cox analysis and three types of prognostic index-adjusted analysis of MR based on ER status. Forest plots displaying univariate Cox’s analysis of EPOR mRNA expression and the risk of MR in ER+ (A) and ER- (D) breast cancer patients; Kaplan-Meier curves of EPOR mRNA expression and MR-free survival in ER+ (B) and ER- (E) breast cancer patients; three types (NPI, AOL and proliferation) of prognostic index-adjusted analysis of the correlation between EPOR mRNA expression and the risk of MR in ER+ (C) and ER- (F) breast cancer patients. Data mining was done by bc- GenExMiner v4.1.|
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3.4. EPOR univariate Cox regression analysis and adjusted analyses of AE based on ER status
Prognostic significance of EPOR mRNA on AE was examined among the breast cancer patients with different ER status. As shown in [Figure 3]A, a total of 31 studies including 3 631 patients were searched to evaluate the relationship between EPOR mRNA level and AR risk in ER+ BRCA patients. The univariate Cox regression analysis demonstrated that high EPOR mRNA level was dramatically related to a lower risk of AE (HR: 0.87, P =0.000 7; [Figure 3]A and also a better AE-free survival (HR: 0.88, 95%CI: 0.78-0.99, P =0.029 9; [Figure 3]B. Besides, NPI-, AOL- and proliferation- adjusted analyses were further performed [Figure 3]E,[Figure 3]F,[Figure 3]G which showed that the significant impact of EPOR mRNA level on AE risk mainly in the ER+ combined N+ subgroup, but not in the ER+ combined N- subgroup. As for ER- patients, a total of 27 studies including 1 394 patients were searched to evaluate the significance of EPOR mRNA level on MR risk [Figure 3]C. The results revealed no significant correlation both in univariate Cox regression analysis [Figure 3]D and NPI-, AOL- and proliferation- adjusted analyses [Figure 3]H.
|Figure 3: EPOR univariate Cox analysis and three types of prognostic index-adjusted analysis of AE based on ER status.|
Forest plots displaying univariate Cox’s analysis of EPOR mRNA expression and the risk of AE in ER+ (A) and ER- (C) breast cancer patients; Kaplan-Meier curves of EPOR mRNA expression and AE-free survival in ER+ (B) and ER- (D) breast cancer patients; three types (NPI, AOL and proliferation) of prognostic index-adjusted analysis of the correlation between EPOR mRNA expression and the risk of AE in ER+ (E) and ER- (H) breast cancer patients; in ER+ patients, subgroup analysis was further made on the basis of nodal- positive (F) or negative (G) status. Data mining was done by bc-GenExMiner v4.1.
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3.5. EPOR univariate Cox regression analysis of AE based on the molecular subtypes of SSP and SCM
Next, the prognostic significance of EPOR mRNA in breast cancer patients was evaluated under different molecular subtypes. As shown in [Table 3], by using the SSP classification, high EPOR mRNA level was significantly related to decreased risk of AE in Luminal B breast cancer (HR: 0.82, 95%CI: 0.71-0.94, P =0.005 9), while no relationship was detected in basal-like, HER2+, Luminal A and normal basal-like subtypes. Moreover, to investigate the reliability of the results on the basis of SSP molecular subtype, EPOR univariate Cox analysis by SCM molecular subtype was done further. Similar to previous results, high EPOR mRNA level was significantly related to decreased risk in ER+/HER2-high proliferation group (HR: 0.86, 95%CI: 0.76-0.97, P =0.0152; [Table 4], but not in ER-/HER2-, HER2+ or ER+/HER2- low proliferation group [Table 4].
| 4. Discussion|| |
Treatment of cancer patients with recombinant human erythropoiesis stimulating agents (rhESA) reduces transfusion requirements and improves quality of life ,,. Anemia prevention is pivotal with a view to hypoxia-driven tumor progression. Nevertheless, the negative outcomes of high-dose rhESA therapy trials on patients with breast or head and neck cancers have raised concern that EPO may boost tumor growth. A prerequisite for effects of EPO is the existence of functional EPOR. Previous studies have provided conflicting results,, which may be partly due to nonspecificity of the antibodies used for detection of EPOR protein,. Therefore, to avoid the bias induced by the protein level detection of EPOR, bioinformatic mining method was performed to explore the expression level of EPOR mRNA in breast cancer and its potential prognostic significance. First, TCGA and GTEx data in GEPIA was used to found surprisingly that EPOR mRNA was dramatically downregulated in BRCA (1 085 cases) compared to normal tissues (291 cases). Then, in order to further know whether or not significantly differential expression levels of EPOR mRNA existed in breast cancer patients based on different kinds of classified parameters, subgroup analysis was employed by bc-GenExMiner v4.1. The findings revealed that there were remarkably differential expression levels of EPOR mRNA between the favorable prognostic parameter group and unfavorable prognostic parameter group. The differential expression levels of EPOR mRNA in each subgroup were listed as follows: ER+ > ER-, PR+ > PR-, NPI1 > NPI2 > NPI3, SBR1 > SBR2 > SBR3, Not basal-like >Basal-like, Not basal-like and not TNBC >Basal-like and TNBC and Not TNBC >TNBC, respectively. As we known, breast cancer patients with the above favorable prognostic parameters were to be considered commonly had a better survival time ,,,. Thus, these results suggested that high EPOR mRNA level might be served as a protective role in breast cancer patients for longer survival. Second, the subsequent validation analyses were performed to investigate whether or not differential expression levels of EPOR mRNA were associated with the risk of MR and AE or MR-free and AE-free survival of breast cancer patients. Consistent with previous hypothesis, we found that high EPOR mRNA expression in ERm or ER+ patients (any type of N status) was remarkably related to decreased the risk of MR and AE. Simultaneously, ER+ patients with high EPOR mRNA level also had much more better MR- free and AE-free survival than those with low EPOR mRNA level. However, no similar phenomenon was detected in patients with ER-. Besides, NPI-, AOL- and proliferation- adjusted analyses were further performed to verify the above findings and the results were consistent. Additionally, univariate Cox analysis of AE was done to evaluate the prognostic significance of EPOR in BRCA patients based on SSP or SCM molecular subtypes. The results showed that high EPOR mRNA level was significantly associated with decreased risk of AE in BRCA patients with Luminal B or ER+/HER2- high proliferation group under SSP and SCM classification, respectively. Taken together, the above findings suggested that high EPOR mRNA level might be a significantly favorable indicator to predict low risk of MR and AE or longer survival in ER+ breast cancer patients.
In conclusion, the present bioinformatic mining findings suggested that EPOR mRNA level might be a significant indicator to predict the risk of MR and AE in ER+ breast cancer patients. In future, this interesting observation is worthy of deeper exploration and validation from the aspect of real fundamental experiments and clinical trials.
Conflict of interest statement
The authors declare that they have no conflict of interest.
This study was supported by the Science and Technology Research Project of Anhui Province (No. 1704a0802148).
| References|| |
Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin
Xu H, Yu S, Liu Q, Yuan X, Mani S, Pestell RG, et al.
Recent advances of highly selective CDK4/6 inhibitors in breast cancer. J Hematol Oncol
Shan M, Yin H, Li J, Li X, Wang D, Su Y, et al.
Detection of aberrant methylation of a six-gene panel in serum DNA for diagnosis of breast cancer. Oncotarget
Baldwin RM, Haghandish N, Daneshmand M, Amin S, Paris G, Falls TJ, et al.
Protein arginine methyltransferase 7 promotes breast cancer cell invasion through the induction of MMP9 expression. Oncotarget
Sinclair AM, Coxon A, McCaffery I, Kaufman S, Paweletz K, Liu L, et al.
Functional erythropoietin receptor is undetectable in endothelial, cardiac, neuronal, and renal cells. Blood
Leyland-Jones B, BEST Investigators and Study Group. Breast cancer trial with erythropoietin terminated unexpectedly. Lancet Oncol
Henke M, Laszig R, Rübe C, Schäfer U, Haase KD, Schilcher B, et al.
Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial. Lancet
Julius A, Desai A, Yung RL. Recombinant human erythropoietin stimulates melanoma tumor growth through activation of initiation factor eIF4E. Oncotarget
Chan KK, Matchett KB, Coulter JA, Yuen HF, McCrudden CM, Zhang SD, et al.
Erythropoietin drives breast cancer progression by activation of its receptor EPOR. Oncotarget
Ilkovi ová L, Trošt N, Szentpéteriová E, Solár P, Komel R, Debeljak N. Overexpression of the erythropoietin receptor in RAMA 37 breast cancer cells alters cell growth and sensitivity to tamoxifen. Int J Oncol
Miao S, Wang SM, Cheng X, Li YF, Zhang QS, Li G, et al.
Erythropoietin promoted the proliferation of hepatocellular carcinoma through hypoxia induced translocation of its specific receptor. Cancer Cell Int
Sinclair AM, Rogers N, Busse L, Archibeque I, Brown W, Kassner PD, et al.
Erythropoietin receptor transcription is neither elevated nor predictive of surface expression in human tumour cells. Br J Cancer
Swift S, Ellison AR, Kassner P, McCaffery I, Rossi J, Sinclair AM, et al.
Absence of functional EpoR expression in human tumor cell lines. Blood
Küster O, Simon P, Mittelbronn M, Tabatabai G, Hermann C, Strik H, et al.
Erythropoietin receptor is expressed in meningiomas and lower levels are associated with tumour recurrence. Neuropathol Appl Neurobiol
Frille A, Leithner K, Olschewski A, Olschewski H, Wohlkönig C, Hrzenjak A. No erythropoietin-induced growth is observed in non-small cell lung cancer cells. Int J Oncol
Elliott S, Swift S, Busse L, Scully S, Van G, Rossi J, et al.
Epo receptors are not detectable in primary human tumor tissue samples. PLoS One
Laugsch M, Metzen E, Svensson T, Depping R, Jelkmann W. Lack of functional erythropoietin receptors of cancer cell lines. Int J Cancer
Fandrey J. Erythropoietin receptors on tumor cells: what do they mean? Oncologist
(Suppl 3): 16-20.
Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res
Jézéquel P, Campone M, Gouraud W, Guérin-Charbonnel C, Leux C, Ricolleau G, et al.
bc-GenExMiner: an easy-to-use online platform for gene prognostic analyses in breast cancer. Breast Cancer Res Treat
Jézéquel P, Frénel JS, Campion L, Guérin-Charbonnel C, Gouraud W, Ricolleau G, et al.
bc-GenExMiner 3.0: new mining module computes breast cancer gene expression correlation analyses. Database (Oxford)
van de Vijver MJ, He YD, van’t Veer LJ, Dai H, Hart AA, Voskuil DW, et al.
A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med
Collins KAL, Stuhlmiller TJ, Zawistowski JS, East MP, Pham TT, Hall CR, et al.
Proteomic analysis defines kinase taxonomies specific for subtypes of breast cancer. Oncotarget
Ma XJ, Wang Z, Ryan PD, Isakoff SJ, Barmettler A, Fuller A, et al.
A two-gene expression ratio predicts clinical outcome in breast cancer patients treated with tamoxifen. Cancer Cell
Minn AJ, Gupta GP, Siegel PM, Bos PD, Shu W, Giri DD, et al.
Genes that mediate breast cancer metastasis to lung. Nature
Pawitan Y, Bjöhle J, Amler L, Borg AL, Egyhazi S, Hall P, et al.
Gene expression profiling spares early breast cancer patients from adjuvant therapy: derived and validated in two population-based cohorts. Breast Cancer Res
Wang Y, Klijn JG, Zhang Y, Sieuwerts AM, Look MP, Yang F, et al.
Gene-expression profiles to predict distant metastasis of lymph-node- negative primary breast cancer. Lancet
Weigelt B, Hu Z, He X, Livasy C, Carey LA, Ewend MG, et al.
Molecular portraits and 70-gene prognosis signature are preserved throughout the metastatic process of breast cancer. Cancer Res
Bild AH, Yao G, Chang JT, Wang Q, Potti A, Chasse D, et al.
Oncogenic pathway signatures in human cancers as a guide to targeted therapies. Nature
Chin K, DeVries S, Fridlyand J, Spellman PT, Roydasgupta R, Kuo WL, et al.
Genomic and transcriptional aberrations linked to breast cancer pathophysiologies. Cancer Cell
Ivshina AV, George J, Senko O, Mow B, Putti TC, Smeds J, et al.
Genetic reclassification of histologic grade delineates new clinical subtypes of breast cancer. Cancer Res
Chin SF, Teschendorf AE, Marioni JC, Wang Y, Barbosa-Morais NL, Thorne NP, et al.
High-resolution aCGH and expression profiling identifies a novel genomic subtype of ER negative breast cancer. Genome Biol
Desmedt C, Piette F, Loi S, Wang Y, Lallemand F, Haibe-Kains B, et al.
Strong time dependence of the 76-gene prognostic signature for node-negative breast cancer patients in the TRANSBIG multicenter independent validation series. Clin Cancer Res
Loi S, Haibe-Kains B, Desmedt C, Lallemand F, Tutt AM, Gillet C, et al.
Definition of clinically distinct molecular subtypes in estrogen receptorpositive breast carcinomas through genomic grade. J Clin Oncol
Minn AJ, Gupta GP, Padua D, Bos P, Nguyen DX, Nuyten D, et al.
Lung metastasis genes couple breast tumor size and metastatic spread. Proc Natl Acad Sci U S A
2007; 104(16): 6740-6745.
Zhou Y, Yau C, Gray JW, Chew K, Dairkee SH, Moore DH, et al.
Enhanced NF kappa B and AP-1 transcriptional activity associated with antiestrogen resistant breast cancer. BMC Cancer
Anders CK, Acharya CR, Hsu DS, Broadwater G, Garman K, Foekens JA, et al.
Age-specific differences in oncogenic pathway deregulation seen in human breast tumors. PLoS One
Chanrion M, Negre V, Fontaine H, Salvetat N, Bibeau F, Mac Grogan G, et al.
A gene expression signature that can predict the recurrence of tamoxifen-treated primary breast cancer. Clin Cancer Res
Loi S, Haibe-Kains B, Desmedt C, Wirapati P, Lallemand F, Tutt AM, et al.
Predicting prognosis using molecular profiling in estrogen receptorpositive breast cancer treated with tamoxifen. BMC Genomics
Schmidt M, Böhm D, von Törne C, Steiner E, Puhl A, Pilch H, et al.
The humoral immune system has a key prognostic impact in node-negative breast cancer. Cancer Res
Calabrò A, Beissbarth T, Kuner R, Stojanov M, Benner A, Asslaber M, et al.
Effects of infiltrating lymphocytes and estrogen receptor on gene expression and prognosis in breast cancer. Breast Cancer Res Treat
Desmedt C, Giobbie-Hurder A, Neven P, Paridaens R, Christiaens MR, Smeets A, et al.
The Gene expression Grade Index: a potential predictor of relapse for endocrine-treated breast cancer patients in the BIG 1-98 trial. BMC Med Genomics
Zhang Y, Sieuwerts AM, McGreevy M, Casey G, Cufer T, Paradiso A, et al.
The 76-gene signature defines high-risk patients that benefit from adjuvant tamoxifen therapy. Breast Cancer Res Treat
Li Y, Zou L, Li Q, Haibe-Kains B, Tian R, Li Y, et al.
Amplification of LAPTM4B and YWHAZ contributes to chemotherapy resistance and recurrence of breast cancer. Nat Med
Sircoulomb F, Bekhouche I, Finetti P, Adélaïde J, Ben Hamida A, Bonansea J, et al.
Genome profiling of ERBB2-amplified breast cancers. BMC Cancer
Buffa FM, Camps C, Winchester L, Snell CE, Gee HE, Sheldon H, et al.
microRNA-associated progression pathways and potential therapeutic targets identified by integrated mRNA and microRNA expression profiling in breast cancer. Cancer Res
Dedeurwaerder S, Desmedt C, Calonne E, Singhal SK, Haibe-Kains B, Defrance M, et al.
DNA methylation profiling reveals a predominant immune component in breast cancers. EMBO Mol Med
Filipits M, Rudas M, Jakesz R, Dubsky P, Fitzal F, Singer CF, et al.
A new molecular predictor of distant recurrence in ER-positive, HER2- negative breast cancer adds independent information to conventional clinical risk factors. Clin Cancer Res
Hatzis C, Pusztai L, Valero V, Booser DJ, Esserman L, Lluch A, et al.
A genomic predictor of response and survival following taxane- anthracycline chemotherapy for invasive breast cancer. JAMA
Kao KJ, Chang KM, Hsu HC, Huang AT. Correlation of microarray- based breast cancer molecular subtypes and clinical outcomes: implications for treatment optimization. BMC Cancer
Sabatier R, Finetti P, Cervera N, Lambaudie E, Esterni B, Mamessier E, et al.
A gene expression signature identifies two prognostic subgroups of basal breast cancer. Breast Cancer Res Treat
Wang DY, Done SJ, McCready DR, Boerner S, Kulkarni S, Leong WL. A new gene expression signature, the ClinicoMolecular Triad Classification, may improve prediction and prognostication of breast cancer at the time of diagnosis. Breast Cancer Res
Kuo WH, Chang YY, Lai LC, Tsai MH, Hsiao CK, Chang KJ, et al.
Molecular characteristics and metastasis predictor genes of triple-negative breast cancer: a clinical study of triple-negative breast carcinomas. PLoS One
Nagalla S, Chou JW, Willingham MC, Ruiz J, Vaughn JP, Dubey P, et al.
Interactions between immunity, proliferation and molecular subtype in breast cancer prognosis. Genome Biol
Rizzo JD, Lichtin AE, Woolf SH, Seidenfeld J, Bennett CL, Cella D, et al.
Use of epoetin in patients with cancer: evidence-based clinical practice guidelines of the American Society of Clinical Oncology and the American Society of Hematology. Blood
Glaspy JA. Cancer patient survival and erythropoietin. J Natl Compr Canc Netw
Varlotto J, Stevenson MA. Anemia, tumor hypoxemia, and the cancer patient. Int JRadiat Oncol Biol Phys
Hardee ME, Arcasoy MO, Blackwell KL, Kirkpatrick JP, Dewhirst MW. Erythropoietin biology in cancer. Clin Cancer Res
Alobaedi OH, Talib WH, Basheti IA. Antitumor effect of thymoquinone combined with resveratrol on mice transplanted with breast cancer. Asian Pac J Trop Med
Zhou YF, Sun Q, Zhang YJ, Wang GM, He B, Qi T, et al.
Targeted inhibition of Notch1 gene enhances the killing effects of paclitaxel on triple negative breast cancer cells. Asian Pac J Trop Med
Nicolini A, Ferrari P, Duffy MJ. Prognostic and predictive biomarkers in breast cancer: Past, present and future. Semin Cancer Biol
2017; doi: 10.1016/j.semcancer.2017.08.010
Fragomeni SM, Sciallis A, Jeruss JS. Molecular subtypes and local- regional control of breast cancer. Surg Oncol Clin N Am
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4]