Marker For ER-positive Breast Cancer Research Articles

MICAL-L2, as an estrogen-responsive gene, is involved in ER-positive breast cancer cell progression and tamoxifen sensitivity via the AKT/mTOR pathway

Endocrine treatment, particularly tamoxifen, has shown significant improvement in the prognosis of patients with estrogen receptor-positive (ER-positive) breast cancer. However, the clinical utility of this treatment is often hindered by the development of endocrine resistance. Therefore, a comprehensive understanding of the underlying mechanisms driving ER-positive breast cancer carcinogenesis and endocrine resistance is crucial to overcome this clinical challenge. In this study, we investigated the expression of MICAL-L2 in ER-positive breast cancer and its impact on patient prognosis. We observed a significant upregulation of MICAL-L2 expression in ER-positive breast cancer, which correlated with a poorer prognosis in these patients. Furthermore, we found that estrogen-ERβ signaling promoted the expression of MICAL-L2. Functionally, our study demonstrated that MICAL-L2 not only played an oncogenic role in ER-positive breast cancer tumorigenesis but also influenced the sensitivity of ER-positive breast cancer cells to tamoxifen. Mechanistically, as an estrogen-responsive gene, MICAL-L2 facilitated the activation of the AKT/mTOR signaling pathway in ER-positive breast cancer cells. Collectively, our findings suggest that MICAL-L2 could serve as a potential prognostic marker for ER-positive breast cancer and represent a promising molecular target for improving endocrine treatment and developing therapeutic approaches for this subtype of breast cancer.

Anti-Tumor Activity and Underlying Mechanism of Phomoxanthone B in MCF7 Cells.

Xanthones are a class of heterocyclic natural products, which are promising sources of anti-cancer leads. Phomoxanthone B (PXB) and Phomoxanthone A(PXA)are xanthone dimers. PXA is wellstudied as an anti-cancer agent, but PXB is not. In our study, PXB was isolated from the endophytic fungus Phomopsis sp. By254. The purpose of this study was to identify the underlying anti-tumor mechanisms of PXB in breast cancer MCF7 cell line. Apoptosis, cell cycle, proliferation, invasion, and migration assays were used to assess the anti-tumor activity of PXB. RNA sequencing was used to analyze the effect of PXB treatment on gene expression in MCF7 cells. PXB showed cytotoxicity towards a variety of tumor cells, especially MCF7 cells. PXB inhibited the migration and invasion, arrested cell cycle at G2/M phase, and induced apoptosis associated with caspase-3 activation in MCF7 cells. The detailed transcriptome analysis revealed that PXB affected several pathways related to tumorigenesis, metabolisms, and oxidative phosphorylation in MCF7 cells. KEGG transcriptome analysis revealed that PXB upregulated pro-survival signal pathways, such as MAPK, PI3K-AKT, and STAT3 pathways. We found that PXB also significantly upregulated the expression of IL24, DDIT3, and XAF1, which may contribute to PXB-induced apoptosis. We further found that PXB may downregulate oxidative phosphorylation by decreasing the expression of electron transport chain genes, especially MT-ND1, which is a potential unfavorable prognostic marker for ER-positive breast cancer. PXB exerts strong cytotoxicity against human tumor cells and has a potential for ER-positive breast cancer treatment.

ΔKi67 proliferation index as independent predictive and prognostic factor of outcome in luminal breast cancer: data from neoadjuvant letrozole-based treatment.

A key tool for monitoring breast cancer patients under neoadjuvant treatment is the identification of reliable predictive markers. Ki67 has been identified as a prognostic and predictive marker in ER-positive breast cancer. Ninety ER-positive, HER2 negative locally advanced breast cancer patients received letrozole (2.5 mg daily) and cyclophosphamide (50 mg daily) with/without Sorafenib (400 mg/bid daily) for 6 months before undergoing surgery. Ki67 expression and tumor size measured with caliber were determined at baseline, after 30 days of treatment and at the end of treatment. Patients were assigned to a clinical response category according to Response Evaluation Criteria in Solid Tumors, both at 30 days and before surgery and further classified as high-responder and low-responder according to the median variation of Ki67 values between biopsy and 30 days and between biopsy and surgery time. The predictive role of Ki67 and its changes with regard to clinical response and survival was analyzed. No differences in terms of survival outcomes emerged between the arms of treatment, while we observed a higher percentage of women with progression or stable disease in arm with the combination containing Sorafenib (20.5% vs 7.1%, p = 0.06). Clinical complete responders experienced a greater overall variation in Ki67 when compared with partial responders and patients with progressive/stable disease (66.7% vs 30.7%, p = 0.009). High responders showed a better outcome than low responders in terms of both disease-free survival (p = 0.009) and overall survival (p = 0.002). ΔKi67 score evaluated between basal and residual tumor at definitive surgery showed to be highly predictive of clinical complete response, and a potential parameter to be used for predicting disease-free survival and overall survival in luminal breast cancer treated with neoadjuvant endocrine-based therapy.

An ER-associated miRNA signature predicts prognosis in ER-positive breast cancer.

BackgroundBreast cancer patients with positive estrogen receptor (ER) have a better prognosis. However, no prognostic miRNA signature was reported in the ER-positive breast cancer. The aim of the study was to identify and assess the prognostic significance of a miRNA signature in ER-positive breast cancer.MethodsTwo cohorts from The Cancer Genome Atlas (TCGA) dataset were used as training (n =596) and testing set (n =319). Differential expression profiling was identified in the training set. And the prognostic value of the miRNA signature was then assessed in the two cohorts.ResultsA total of 14 miRNAs were observed to be associated with the status of ER by significance analysis of microarrays (SAM) in the training set. Patients were characterized as high score or low score group according to the calculated risk scores from each miRNA. And patients in high score group had worse overall survival compared with those in low score group both in the training and testing set.ConclusionsOur study revealed a miRNA signature including 14 miRNAs associated with ER status which could act as a prognostic marker in ER-positive breast cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-014-0094-5) contains supplementary material, which is available to authorized users.

FOXA1 expression after neoadjuvant chemotherapy is a prognostic marker in estrogen receptor-positive breast cancer

Recent studies have indicated that the response to chemotherapy and the prognostic impact of a pathological complete response (pCR) after neoadjuvant chemotherapy differ among breast cancer subtypes. Predictors of response to chemotherapy and prognostic factors for survival might be different in estrogen receptor (ER)-positive breast cancer. Women with Stage II to III ER-positive HER2-negative breast cancer treated with anthracycline and taxane-containing neoadjuvant chemotherapy between 2003 and 2011 were retrospectively analyzed. Expression of forkhead box A1 (FOXA1), B cell lymphoma 2 (BCL2) and microtubule-associated protein tau (MAPT) as well as ER, progesterone receptor, HER2 and Ki67 was examined by immunohistochemistry in pre- and post-treatment specimens. Factors predictive of response to neoadjuvant chemotherapy and distant disease-free survival were analyzed. Tumor grade was positively correlated with Ki67 expression. Expression levels of ER were positively correlated with expression levels of HER2, BCL2, FOXA1 and MAPT in pre-treatment tumors. The Ki67 labeling index was the only factor that was significantly associated with clinical response measured by the reduction of tumor volume and pCR. Lymph node status, expression of ER before neoadjuvant chemotherapy and expression of FOXA1 after neoadjuvant chemotherapy were significantly associated with distant disease-free survival, both by univariate and multivariate analyses. Patients with ER-positive HER2-negative breast cancer should be selected for neoadjuvant chemotherapy. FOXA1 expression could be a prognostic marker in ER-positive breast cancer.

Aurora kinase A outperforms Ki67 as a prognostic marker in ER-positive breast cancer

Background:Proliferation has emerged as a major prognostic factor in luminal breast cancer. The immunohistochemical (IHC) proliferation marker Ki67 has been most extensively investigated but has not gained widespread clinical acceptance.Methods:We have conducted a head-to-head comparison of a panel of proliferation markers, including Ki67. Our aim was to establish the marker of the greatest prognostic utility. Tumour samples from 3093 women with breast cancer were constructed as tissue microarrays. We used IHC to detect expression of mini-chromosome maintenance protein 2, Ki67, aurora kinase A (AURKA), polo-like kinase 1, geminin and phospho-histone H3. We used a Cox proportional-hazards model to investigate the association with 10-year breast cancer-specific survival (BCSS). Missing values were resolved using multiple imputation.Results:The prognostic significance of proliferation was limited to oestrogen receptor (ER)-positive breast cancer. Aurora kinase A emerged as the marker of the greatest prognostic significance in a multivariate model adjusted for the standard clinical and molecular covariates (hazard ratio 1.3; 95% confidence interval 1.1–1.5; P=0.005), outperforming all other markers including Ki67.Conclusion:Aurora kinase A outperforms other proliferation markers as an independent predictor of BCSS in ER-positive breast cancer. It has the potential for use in routine clinical practice.

FOXA1 is an independent prognostic marker for ER-positive breast cancer

Forkhead box protein A1 (FOXA1) is a "pioneer factor" that plays a role in controlling nearly 50% of estrogen receptor target genes. FOXA1 expression correlates with estrogen receptor (ER)-positivity especially in luminal subtype A breast cancers. The aim of this study was to investigate the precise role of FOXA1 in breast cancer using a large population-based cohort. Nuclear expression of FOXA1 was analyzed in a tissue microarray of 4,444 invasive breast cancer cases using immunohistochemistry and correlated with clinicopathologic variables using previously described methods and cutoff points. The entire cohort was equally divided into a training and validation set. All survival analyses were performed using a previously defined cutoff (3) for validation. Additional X-tile analysis performed to analyze prognostic effects of low and high FOXA1 levels identified 24 as a cutoff. Bonferroni-Holmes test was used as appropriate. FOXA1 expression significantly correlated positively with markers of good prognosis or ER-positivity, and negatively with tumor size, tumor grade, nodal status, Ki67, HER2 expression, and basal subtype (each P value <0.0001). In both survival analyses, FOXA1 was a significant predictor of breast cancer-specific survival (P<0.0001) and relapse-free survival (P<0.0001). FOXA1 was also an independent predictor of breast cancer-specific survival at 10years using both cutoffs. Among the ER-positive subgroup treated with tamoxifen, FOXA1 was an independent prognostic marker using the 24 cutoff (P=0.030). FOXA1 is a significant marker of good prognosis in breast cancer; it also identifies a subset of ER-positive tamoxifen treated patients at low risk of recurrence.

Expression of forkhead-box protein A1 (FOXA1) as a significant prognostic and predictive marker for ER-positive breast cancer.

608 Background: One of the major issues associated with the breast cancer therapy is how to determine the indication of adjuvant chemotherapy for the patients with luminal subtypes. Multigene prognosis assays such as Oncotype Dx are excellent techniques, however, there are some limitations in their clinical use, high cost and patent problems. The transcription factor network composed of ER, Forkhead-box protein A1 (FOXA1), and GATA-binding protein 3 (GATA3) is necessary for the ERα functional signature specific to luminal type, and the presence of an intact GATA-3/FOXA1/ ER network appears to be critical for the hormone responsive phenotype. This study evaluated the usefulness of the expression of FOXA1 as a prognostic and predictive marker for ER-positive breast cancer. Methods: We analyzed the expression of FOXA1, GATA3 by immunohistochemical analyses in 155 cases of primary breast cancer. We evaluated the association of the expression of these proteins with clinicopathologic characteristics and prognosis, especially in ER-positive cases. Results: (1) FOXA1 and GATA3 expressions correlated positively (p < 0.0001). (2) FOXA1 expression was positively correlated with ER (p < 0.0001) and PR (p = 0.0003), and inversely correlated with nuclear grade (p = 0.0004) and Ki 67 index (p < 0.0001). (3) FOXA1 expression was significantly correlated with the better prognosis in all (p = 0.0104) and in ER-positive cases (p = 0.0031), but no relationship in ER-negative cases. In addition, low FOXA1 expression was significantly associated with the shorter disease-free survival in patients who received adjuvant endocrine therapy (p = 0.0105). On the other hand, Ki-67 index was associated with the poor prognosis, especially in ER-negative cases, not in ER-positive cases. Conclusions: FOXA1 expression is significantly associated with the good prognosis, especially in ER-positive breast cancer. This study suggests that FOXA1 expression may be used as a prognostic and predictive marker for ER-positive breast cancer, which can be used as a more cost-effective strategy to select the patients in whom chemotherapy may be omitted. No significant financial relationships to disclose.

The Secretory Small GTPase Rab27B Regulates Invasive Tumor Growth and Metastasis through Extracellular Heat Shock Protein 90α.

Abstract Background: Vesicle exocytosis, controlled by secretory GTPases such as Rab27B, delivers critical pro-invasive factors into the tumor microenvironment. The biological role and expression status of Rab27B in breast cancer was unknown.Methods: Rab27B was studied in human breast cancer cells (MCF-7, T47D, ZR75.1) using GFP-fusion constructs, including Rab27A and Rab27B point mutants defective in GTP-binding or geranylgeranylation. In cell culture, cell-cycle progression was evaluated by flow cytometry and Western blotting, invasion was assessed using Matrigel and collagen type I substrates. Orthotopic tumor growth, local invasion and metastasis were analyzed in mouse xenograft models. Mass spectrometry was performed to identify Rab27B-secreted pro-invasive factors. Rab27B levels in clinical breast cancer were analyzed by quantitative reverse transcription-polymerase chain reaction (n=20) and immunohistochemistry (n=60). Statistical tests were two-sided.Results: Rab27B-upregulation promoted G1/S phase cell cycle transition, F-actin reorganization and invasion in cell culture, and invasive tumor growth and peritoneal metastasis in a xenograft mouse model (at 10 weeks, survival of MCF-7 GFP vs GFP-Rab27B injected mice was 100% vs 62.5%, P=0.0307). Proteomic analysis of purified Rab27B-secretory vesicles and the secretome of Rab27B-expressing breast cancer cells identified heat shock protein (HSP)90α as key pro-invasive factor. HSP90α secretion occurred in a Rab27B-dependent manner and was required for matrix metalloproteinase-2 activation. All Rab27B-mediated functional responses were GTP- and geranylgeranyl-dependent. In clinical samples, upregulation of endogenous Rab27B mRNA and protein correlated with lymph node metastasis (P=0.0002) and differentiation grade (P=0.0014) in estrogen receptor (ER)-positive human breast tumors.Conclusions: Rab27B, a new prognostic marker for ER-positive breast cancer, regulates invasive growth and metastasis. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6144.

Stat5 is a prognostic marker for ER-positive breast cancer

Stat5 is a prognostic marker for ER-positive breast cancer

Stat5 expression predicts response to endocrine therapy and improves survival in estrogen receptor-positive breast cancer

Constitutively activated signal transducers and activators of transcription (Stats), in particular Stat3 and Stat5, have been demonstrated to directly contribute to oncogenesis by stimulating cell proliferation and preventing apoptosis in various cancers. Stat3 is essential in mammary gland epithelial cell apoptosis and involution, whereas Stat5 is well established as a key factor in mammary epithelial cell growth and differentiation. Crosstalk between Stats and estrogen receptor (ER) has been demonstrated by several laboratories and we have focused on the role of Stat5 in ER-positive breast cancer. Using immunohistochemical techniques, we examined the expression of Stat3 and Stat5 in 517 human breast cancer tissues and analyzed their significance for prognosis and prediction of response to endocrine therapy. Stat5 expression was significantly correlated with histological grade (P<0.0001), ER (P=0.02), and progesterone receptor (P=0.026) expression. There was no difference between Stat3 expression and clinicopathological factors. In 346 patients with ER-positive breast cancer, patients with Stat5 positive tumors had significantly increased overall survival (P=0.0009) in multivariate analysis. There were 70 patients who received endocrine therapy as first-line treatment for metastatic breast cancer at relapse. The patients whose primary breast tumors were Stat5 positive, had significantly better response to endocrine therapy (P=0.04), and longer survival after relapse (P=0.0003), than those whose tumors were Stat5 negative. The present study demonstrates for the first time that Stat5 is a predictive factor for endocrine therapy response and a strong prognostic molecular marker in ER-positive breast cancer. Our data suggest that the expression of Stat5 is helpful in selecting patients who may benefit from endocrine therapy.