scholarly journals A Novel Group of Genes that Causes Endocrine Resistance in Breast Cancer Identified by Dynamic Gene Expression Analysis

2021 ◽  
Author(s):  
Arvand Asghari ◽  
Katherine Wall ◽  
Michael Gill ◽  
Natascha Del Vecchio ◽  
Farnaz Allahbakhsh ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Endocrine Resistance ◽  
Gene Mutations ◽  
Therapeutic Approaches ◽  
Resistance Development ◽  
Development Of Resistance ◽  
Er Positive ◽  
Underlying Causes ◽  
Positive Breast Cancer

Abstract Breast cancer (BC) is the most common type of cancer and the second leading cancer-related cause of death in women worldwide. Endocrine therapy is an effective therapeutic approach for estrogen receptor (ER)-positive breast cancer; however, in many cases, tumor regrowth occurs after the therapy and the tumor becomes unresponsive anymore. While some gene mutations contribute to the resistance in some patients, the underlying causes of the resistance to endocrine therapies are mostly undetermined. In this study, we utilized our recently developed statistical approach to investigate the dynamic behavior of gene expression during the development of endocrine resistance and identified a novel group of genes that can be crucial to the development of resistance in BC. The expression of these genes is not only altered in cell models during the endocrine resistance development but also significantly changed in endocrine-resistant patients. Surprisingly, this group of genes was also identified as a group of key candidate genes in triple-negative breast cancer (TNBC), suggesting that endocrine resistance and TNBC share the same mechanisms during their development. Our findings explain some of the genetic underlying reasons for endocrine resistance and provide the potential to develop novel common therapeutic approaches against endocrine-resistant BC and TNBC.

scholarly journals Relationship Between Plasma Estradiol Levels and Estrogen-Responsive Gene Expression in Estrogen Receptor–Positive Breast Cancer in Postmenopausal Women

2010 ◽  
Vol 28 (7) ◽  
pp. 1161-1167 ◽  
Author(s):  
Anita K. Dunbier ◽  
Helen Anderson ◽  
Zara Ghazoui ◽  
Elizabeth J. Folkerd ◽  
Roger A'Hern ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Estrogen Receptor ◽  
Postmenopausal Women ◽  
Multivariable Analysis ◽  
Independent Set ◽  
Breast Cancers ◽  
Plasma Estradiol ◽  
Er Positive ◽  
Positive Breast Cancer

Purpose To determine whether plasma estradiol (E2) levels are related to gene expression in estrogen receptor (ER)–positive breast cancers in postmenopausal women. Materials and Methods Genome-wide RNA profiles were obtained from pretreatment core-cut tumor biopsies from 104 postmenopausal patients with primary ER-positive breast cancer treated with neoadjuvant anastrozole. Pretreatment plasma E2 levels were determined by highly sensitive radioimmunoassay. Genes were identified for which expression was correlated with pretreatment plasma E2 levels. Validation was performed in an independent set of 73 ER-positive breast cancers. Results The expression of many known estrogen-responsive genes and gene sets was highly significantly associated with plasma E2 levels (eg, TFF1/pS2, GREB1, PDZK1 and PGR; P < .005). Plasma E2 explained 27% of the average expression of these four average estrogen-responsive genes (ie, AvERG; r = 0.51; P < .0001), and a standardized mean of plasma E2 levels and ER transcript levels explained 37% (r, 0.61). These observations were validated in an independent set of 73 ER-positive tumors. Exploratory analysis suggested that addition of the nuclear coregulators in a multivariable analysis with ER and E2 levels might additionally improve the relationship with the AvERG. Plasma E2 and the standardized mean of E2 and ER were both significantly correlated with 2-week Ki67, a surrogate marker of clinical outcome (r = −0.179; P = .05; and r = −0.389; P = .0005, respectively). Conclusion Plasma E2 levels are significantly associated with gene expression of ER-positive breast cancers and should be considered in future genomic studies of ER-positive breast cancer. The AvERG is a new experimental tool for the study of putative estrogenic stimuli of breast cancer.

scholarly journals Quantitative Gene Expression by Recurrence Score in ER-Positive Breast Cancer, by Age

2015 ◽  
Vol 32 (12) ◽  
pp. 1222-1236 ◽  
Author(s):  
Sandra M. Swain ◽  
Raquel Nunes ◽  
Carl Yoshizawa ◽  
Megan Rothney ◽  
Amy P. Sing
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Recurrence Score ◽  
Quantitative Gene Expression ◽  
Er Positive ◽  
Positive Breast Cancer

scholarly journals Low residual proliferation after short-term letrozole therapy is an early predictive marker of response in high proliferative ER-positive breast cancer

2011 ◽  
Vol 18 (6) ◽  
pp. 721-730 ◽  
Author(s):  
Philippe L Bedard ◽  
Sandeep K Singhal ◽  
Michail Ignatiadis ◽  
Ian Bradbury ◽  
Benjamin Haibe-Kains ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Clinical Response ◽  
Histological Grade ◽  
Low Grade ◽  
High Grade ◽  
Early Assessment ◽  
Short Term ◽  
Er Positive ◽  
Positive Breast Cancer

The gene expression grade index (GGI) is a 97-gene algorithm that measures proliferation and divides intermediate histological grade tumors into two distinct groups. We investigated the association between early changes in GGI and clinical response to neoadjuvant letrozole and compared this to Ki67 values. The paired gene expression data at the beginning and after 10–14 days of neoadjuvant letrozole treatment were available for 52 post-menopausal patients with estrogen receptor (ER)-positive breast cancer. Baseline values and changes in GGI, Ki67, and RNA expression modules representing oncogenic signaling pathways were compared to sonographic tumor volume changes after 3 months of treatment in the subsets of patients defined by high and low baseline GGI. The clinical response was observed in 80% genomic low-grade (24/30) and 59% genomic high-grade (13/22) tumors (P=0.10). Low residual proliferation after 10–14 days of neoadjuvant letrozole therapy, measured by either GGI or Ki67, was associated with sonographic response in genomic high-grade (GGI, P=0.003; Ki67, P=0.017) but not genomic low-grade (GGI, P=0.25; Ki67, P=1.0) tumors. The analysis of expression modules suggested that sonographic response to letrozole in genomic high-grade tumors was associated with an early reduction in IGF1 signaling (unadjusted P=0.018). The major conclusion of this study is that the early assessment of proliferation after short-term endocrine therapy may be useful to evaluate endocrine responsiveness, particularly in genomic high-grade ER-positive breast cancer.

Correlations of estrogen receptor (ER) related genomic transcription and ER gene expression with increasing AJCC stage of ER-positive breast cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 1044-1044
Author(s):  
E. Andreopoulou ◽  
C. Hatzis ◽  
D. Booser ◽  
V. Valero ◽  
M. J. Wallace ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Stage Iv ◽  
Initial Presentation ◽  
Clinical Samples ◽  
Expression Levels ◽  
Pathologic Stage ◽  
Ajcc Stage ◽  
Er Positive ◽  
Positive Breast Cancer

1044 Background: Advanced stages of ER-positive breast cancer may have decreased tumor dependence on estrogen, possibly due to biological selection and/or progression. The sensitivity to endocrine therapy (SET) index measures transcriptional activity of the ER genomic pathway (165 ER-related genes). We investigated whether expression of genes for receptors ER (ESR1), progesterone receptor (PGR), or HER-2 (ERBB2), the SET index, or a housekeeper gene (GAPDH) vary by stage of ER-positive breast cancer. Methods: We evaluated gene expression profiles (Affymetrix U133 microarrays, Affymetrix, Santa Clara, CA) from 956 patients’ clinical samples of ER-positive breast cancer, including 290 new samples profiled at MDACC and 666 samples from published datasets. Microarray data were uniformly normalized, log-transformed, and expression levels for single genes and the SET index were compared to pathologic AJCC stage (315 patients were stage I, 362 stage IIA, 151 stage IIB, 29 stage III, 27 stage IV at initial presentation, and 72 stage IV previously treated and/or at relapse) using a median ordered regression analysis (p < 0.05 was significant). Results: SET index significantly decreased with advancing pathologic stage (p < 0.001), and PGR expression levels showed a similar, but lesser, effect (p = 0.014). However, expression levels of ESR1 and ERBB2 did not vary by stage. Overall, GAPDH gene expression increased with stage (p < 0.001), but that effect was only observed in stages III and IV. Expression of these genes was not significantly different between stage IV disease at initial presentation or at relapse. Conclusions: Expression levels of ESR1 and ERBB2 receptor genes did not vary, but ER-related genomic transcription (SET index and, to a lesser extent, PGR) declined significantly with increasing pathologic stage. This suggests that ER-positive breast cancer tends to have less transcriptional dependence on estrogen with increasing pathologic stage. The observed increase in expression of GAPDH in stages III and IV might reflect higher metabolic activity in advanced ER-positive breast cancer and deserves further study. [Table: see text]

HER2 FISH ratio cut-points and pathologic complete response (pCR), residual tumor (RT), HER2 status, and survival prediction in HER2-positive breast cancer (BC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e22033-e22033
Author(s):  
R. S. Mehta ◽  
D. Jackson ◽  
T. Schubbert ◽  
D. Hsiang
Keyword(s):  
Breast Cancer ◽  
Pathologic Complete Response ◽  
Endocrine Resistance ◽  
Disease Free Survival ◽  
Survival Prediction ◽  
Her2 Positive ◽  
Cut Point ◽  
Her2 Positive Breast Cancer ◽  
Er Positive ◽  
Positive Breast Cancer

e22033 Background: We demonstrated that pCR is correlated with increasing HER2-FISH ratio, while disease-free survival (DFS) with pCR and ER-positivity in HER2-positive breast cancer treated with trastuzumab (SABCS 2008). It is known that quantitative HER2-FISH ratio correlates with ER levels and HER2-positivity imparts a higher grade in ER-positive BC. Collectively, we hypothesized that combined ER (≥10) and a HER2 ratio cut-point may subdivide HER2-positive BC into pCR predictive subtypes.Methods: Of the 80 HER2-positive (IHC3+/FISH+) BC, quantitative HER2 FISH ratio (widely spread over 1–18.3) and ER correlation was noted (r=0.34, p=0.002). Moreover, HER2 ratio (>4) correlated with higher Ki-67 (r= 0.5, p=0.01) and grade (p trend=0.05) in ER-positive subtype, inferring a biologic cut-point. Results: Of patients with stage I-IV BC treated neoadjuvantly (92% trastuzumab-based), pCR was 0% (0/13) in ER-positive-low-HER2 compared to 77% (10/13, p=0.0001), 75% (24/32, p<0.0001) and 37.5% (3/8, p=0.043) in ER-positive-high-HER2, ER-negative-high-HER2 and ER-negative-low-HER2, respectively. DFS was 100, 90, 80% and 60% (logrank-trend p<0.05) in these 4 subtypes (excluding stage IV), respectively, at a median follow-up of 38 months (range 6–72). In ER-negative subtypes, DFS was 97% and 29% (logrank p=0.0001) in patients with or without pCR; of the six with RT, 0% DFS was noted in four with HER2-negative/HER2-reduced (HER2-R) RT, compared to 100% in the two with unchanged HER2 (p=<0.05, logrank test). In ER-positive subtypes, DFS is 95% overall, and 100% in patients with RT; 7 of 10 tested RT were HER2- R. Conclusions: pCR is crucial and high in ER-negative-high-HER2 and is crucial (but low) in ER-negative-low-HER2-positive BC for improved outcome. Improved DFS is associated with high pCR in ER-positive-high-HER2 BC, but is independent of the low pCR in ER-positive-low-HER2-subtype. Thus, combined HER2 and ER offer improved prediction. In hypothesis generating analysis, HER2-R may underlie relapse in ER-negative subtypes (HER2-basal-transitional-residual), while it may be beneficial in ER-positive subtypes (luminal-B- A-transitional) by reducing HER2-pathway mediated endocrine resistance. [Table: see text]

scholarly journals The ubiquitin ligase RNF181 stabilizes ERα and modulates breast cancer progression

Oncogene ◽  
2020 ◽  
Vol 39 (44) ◽  
pp. 6776-6788
Author(s):  
Jian Zhu ◽  
Xin Li ◽  
Peng Su ◽  
Min Xue ◽  
Yifeng Zang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Cancer Progression ◽  
Ubiquitin Ligase ◽  
Target Gene ◽  
Endocrine Resistance ◽  
Breast Cancer Progression ◽  
Sequencing Analysis ◽  
Target Gene Expression ◽  
Positive Breast Cancer

Abstract ERα positive breast cancer accounts for 70% of breast malignancies. Compared with ERα negative types, ERα positive breast cancer could be effective controlled by endocrine therapy. However, more than half of the patients will develop endocrine resistance, making it an important clinical issue for breast cancer therapy. Endocrine resistance might be caused by multiple alternations, including the components of ERα signaling, during tumor progression. Thus, it is urgent and necessary to uncover the molecular mechanisms that controls ERα expression and stability to improve breast cancer therapeutics. In our current study, we identifies that the ubiquitin ligase RNF181 stabilizes ERα and facilitates breast cancer progression. The expression of RNF181 is correlated with ERα level in human breast tumors and relates to poor survival in endocrine-treated patients. RNF181 depletion inhibits breast cancer progression in vivo and in vitro, reduces ERα protein level and its target gene expression, such as PS2 and GREB1. Unbiased RNA sequencing analysis indicates RNF181 is necessary for ERα signature gene expression in whole genomic level. Immuno-precipitation assays indicate that RNF181 associates with ERα and promotes its stability possibly via inducing ERα K63-linked poly-ubiquitination. In conclusion, our data implicate a non-genomic mechanism by RNF181 via stabilizing ERα protein controls ERα target gene expression linked to breast cancer progression.

scholarly journals Estrogen Receptor (ESR1) mRNA Expression and Benefit From Tamoxifen in the Treatment and Prevention of Estrogen Receptor–Positive Breast Cancer

2011 ◽  
Vol 29 (31) ◽  
pp. 4160-4167 ◽  
Author(s):  
Chungyeul Kim ◽  
Gong Tang ◽  
Katherine L. Pogue-Geile ◽  
Joseph P. Costantino ◽  
Frederick L. Baehner ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Estrogen Receptor ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Tamoxifen Resistance ◽  
Linear Predictor ◽  
Treatment And Prevention ◽  
Er Positive ◽  
Positive Breast Cancer

Purpose Several mechanisms have been proposed to explain tamoxifen resistance of estrogen receptor (ER) –positive tumors, but a clinically useful explanation for such resistance has not been described. Because the ER is the treatment target for tamoxifen, a linear association between ER expression levels and the degree of benefit from tamoxifen might be expected. However, such an association has never been demonstrated with conventional clinical ER assays, and the ER is currently used clinically as a dichotomous marker. We used gene expression profiling and ER protein assays to help elucidate molecular mechanism(s) responsible for tamoxifen resistance in breast tumors. Patients and Methods We performed gene expression profiling of paraffin-embedded tumors from National Surgical Adjuvant Breast and Bowel Project (NSABP) trials that tested the worth of tamoxifen as an adjuvant systemic therapy (B-14) and as a preventive agent (P-1). This was a retrospective subset analysis based on available materials. Results In B-14, ESR1 was the strongest linear predictor of tamoxifen benefit among 16 genes examined, including PGR and ERBB2. On the basis of these data, we hypothesized that, in the P-1 trial, a lower level of ESR1 mRNA in the tamoxifen arm was the main difference between the two study arms. Only ESR1 was downregulated by more than two-fold in ER-positive cancer events in the tamoxifen arm (P < .001). Tamoxifen did not prevent ER-positive tumors with low levels of ESR1 expression. Conclusion These data suggest that low-level expression of ESR1 is a determinant of tamoxifen resistance in ER-positive breast cancer. Strategies should be developed to identify, treat, and prevent such tumors.

scholarly journals Antiestrogenic Effects of the Novel Sphingosine Kinase-2 Inhibitor ABC294640

Endocrinology ◽  
2010 ◽  
Vol 151 (11) ◽  
pp. 5124-5135 ◽  
Author(s):  
James W. Antoon ◽  
Martin D. White ◽  
William D. Meacham ◽  
Evelyn M. Slaughter ◽  
Shannon E. Muir ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Endocrine Resistance ◽  
Sphingosine Kinase ◽  
Hek293 Cells ◽  
Sphingolipid Metabolism ◽  
Cancer Drug ◽  
The Novel ◽  
Er Positive ◽  
Cancer Tumor ◽  
Positive Breast Cancer

Alterations in sphingolipid metabolism have been shown to contribute to the development of endocrine resistance and breast cancer tumor survival. Sphingosine kinase (SK), in particular, is overexpressed in breast cancer and is a promising target for breast cancer drug development. In this study, we used the novel SK inhibitor ABC294640 as a tool to explore the relationship between SK and estrogen (E2) receptor (ER) signaling in breast cancer cells. Treatment with ABC294640 decreased E2-stimulated ERE-luciferase activity in both MCF-7 and ER-transfected HEK293 cells. Furthermore, the inhibitor reduced E2-mediated transcription of the ER-regulated genes progesterone receptor and SDF-1. Competitive receptor-binding assays revealed that ABC294640 binds in the antagonist ligand-binding domain of the ER, acting as a partial antagonist similar to tamoxifen. Finally, treatment with ABC294640 inhibited ER-positive breast cancer tumor formation in vivo. After 15 d of treatment with ABC294640, tumor volume was reduced by 68.4% (P &lt; 0.05; n = 5) compared with control tumors, with no marked weight loss or illness. Taken together, these results provide strong evidence that this novel SK inhibitor, which had not previously been known to interact with E2 signaling pathways, has therapeutic potential in treating ER-positive breast cancer via inhibition of both SK and ER signaling.

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