Estrogen receptor variants in ER-positive basal-type breast cancers responding to therapy like ER-negative breast cancers

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.

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Analysis of Low Estrogen Receptor (ER+) Breast Carcinomas in a Large Community Breast Cancer Center in Northern California

American Journal of Clinical Pathology ◽

10.1093/ajcp/aqab191.051 ◽

2021 ◽

Vol 156 (Supplement_1) ◽

pp. S26-S27

Author(s):

G Bulusu ◽

K Duncan ◽

A Wheeler

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Histological Grade ◽

Statistical Significance ◽

Cancer Center ◽

Pathology Report ◽

Breast Cancers ◽

Breast Carcinomas ◽

Ki 67 ◽

Er Positive

Abstract Introduction/Objective Estrogen Receptor (ER) expression in breast cancers is a crucial factor for endocrine therapy in patients with tumors expressing ER in ≥1% of tumor cells. The 2019 guidelines published by ASCO/CAP states that breast cancers that have a 1% to 10% of cells staining Estrogen Receptor (ER) positive should be reported as ER Low Positive cases. This study aims to address this subset of low-positive ER tumors and compare the clinical features to other known breast cancer subtypes. Methods/Case Report We conducted a retrospective review of a prospectively maintained breast cancer registry from 2013 to 2021 at Mills-Peninsula Medical Center, a Sutter Health Affiliate. The study reviewed patient charts with respect to the pathology report, operative report, chemotherapy regimen, and clinical outcomes. Statistical analyses were conducted using R Project for Statistical Coding, with The Student’s T-test used to compare continuous variables. Two-sided P values less than 0.05 indicate statistical significance. Results (if a Case Study enter NA) Our study identified 1316 cases of invasive breast carcinomas, of which 29 (2.16%) demonstrated ER Low-Positive expression. We aimed to evaluate the clinical and pathological features, such as histological grade, ER, PR, HER-2, Ki-67%, and patient age for these tumors. We found that ER Low-Positive tumors demonstrated higher mean histological grade morphology (2.5 out of 3, p<0.001) that was similar to that of Triple Negative Breast Cancers (TNBC) (3 of 3, p<0.001) than to High ER-Positive (1.6 of 3, p<0.001) cancers. Further observations, through examining proliferation rates by utilizing the Ki-67 index, indicate comparative trends between the ER Low-Positive cohort and the TNBC cohort. Conclusion The results suggest that the ER Low-Positive carcinomas, despite reported as ER-positive cases, present with similar clinicopathological features to those of ER-negative tumors. Through this study and future research, we would like to emphasize a stricter set of guidelines that can be adopted to reduce variability for reporting biomarkers. This standardization will allow oncologists to provide more appropriate treatment options and improve the quality of patient care.

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Serum proteomic profiling distinguishes estrogen receptor (ER) positive and ER negative breast cancers

Journal of Clinical Oncology ◽

10.1200/jco.2005.23.16_suppl.578 ◽

2005 ◽

Vol 23 (16_suppl) ◽

pp. 578-578

Author(s):

M. Sun ◽

J. Lyons-Weiler ◽

A. E. Lokshin ◽

F. Modugno ◽

...

Keyword(s):

Estrogen Receptor ◽

Breast Cancers ◽

Proteomic Profiling ◽

Er Positive

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A novel therapeutic strategy for ER-negative human breast cancers, targeting AP-1 activity

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.14129 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 14129-14129

Author(s):

K. Sakaguchi ◽

H. Nakajima ◽

I. Fujiwara ◽

N. Mizuta ◽

J. Magae

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Cell Lines ◽

Cancer Cell ◽

Breast Cancer Cell ◽

Human Breast Cancer ◽

Human Breast Cancer Cell ◽

Breast Cancers ◽

Human Breast ◽

Er Positive

14129 Background: While agents targeting estrogen receptors are the most effective in adjuvant therapy for human breast cancers expressing estrogen receptor(ER), breast cancers lacking ER are clinically serious, because they are highly malignant and exhibit resistance to the usual anti-cancer drugs, including estrogen receptor-antagonists and DNA breaking agents. Although a transcription factor, AP-1, is known to be related to tumor malignancy including metastasis, invasion and drug-resistance, it remains to be elucidated how AP-1 plays in development and expression of malignant characters of human breast cancers. Methods and Results: Here, we used MX-1, a human breast cancer cell line lacking ER and several ER positive cell lines, to clarify the roles of AP-1 and the therapeutic efficacy of ascochlorin, a newly developed prenylphenol antibiotic on ER-negative breast cancer. We found that MX-1 exhibited higher AP-1 activity and expressed higher levels of c-Jun, c-Fos and Fra-1 when compared with conventional ER-positive human breast cancer cell lines. Consistent with this study in vitro, histological study on human breast cancer tissues suggests that ER-negative cancers express high Fra-1 protein, and that paclitaxel- sensitive cancers express low Fra-1 protein. The ascochlorin, which inhibits AP-1 through the Erk signaling pathway, suppressed the AP-1 activity of MX-1 cells, and selectively killed MX-1 cells, partly due to induction of apoptosis. Moreover, administration of ascochlorin elongated life span of mice intraperitoneally implanted with murine mammary carcinoma cells. Conclusions: Our results suggest that AP-1 is an effective clinical target molecule for the treatment of ER-negative human breast cancer, and that ascochlorin is promising therapeutic agent for these refractory breast cancers. No significant financial relationships to disclose.

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The Histone Demethylase Enzymes KDM3A and KDM4B Co-Operatively Regulate Chromatin Transactions of the Estrogen Receptor in Breast Cancer

Cancers ◽

10.3390/cancers11081122 ◽

2019 ◽

Vol 11 (8) ◽

pp. 1122 ◽

Cited By ~ 5

Author(s):

Jones ◽

Wilson ◽

Thomas ◽

Gaughan ◽

Wade

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Therapeutic Option ◽

Global Gene Expression ◽

Gene Signature ◽

Inhibitory Effect ◽

Breast Cancers ◽

Er Positive ◽

Environment Control ◽

Transcriptional Complex

Many estrogen receptor (ER)-positive breast cancers develop resistance to endocrine therapy but retain canonical receptor signalling in the presence of selective ER antagonists. Numerous co-regulatory proteins, including enzymes that modulate the chromatin environment, control the transcriptional activity of the ER. Targeting ER co-regulators has therefore been proposed as a novel therapeutic approach. By assessing DNA-binding dynamics in ER-positive breast cancer cells, we have identified that the histone H3 lysine 9 demethylase enzymes, KDM3A and KDM4B, co-operate to regulate ER activity via an auto-regulatory loop that facilitates the recruitment of each co-activating enzyme to chromatin. We also provide evidence that suggests that KDM3A primes chromatin for deposition of the ER pioneer factor FOXA1 and recruitment of the ER-transcriptional complex, all prior to ER recruitment, therefore establishing an important mechanism of chromatin regulation involving histone demethylases and pioneer factors, which controls ER functionality. Importantly, we show via global gene-expression analysis that a KDM3A/KDM4B/FOXA1 co-regulated gene signature is enriched for pro-proliferative and ER-target gene sets, suggesting that abrogation of this network could be an efficacious therapeutic strategy. Finally, we show that depletion of both KDM3A and KDM4B has a greater inhibitory effect on ER activity and cell growth than knockdown of each individual enzyme, suggesting that targeting both enzymes represents a potentially efficacious therapeutic option for ER-driven breast cancer.

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Is the Oncotype DX Assay Necessary in Strongly Estrogen Receptor-Positive Breast Cancers?

The American Surgeon ◽

10.1177/000313481107701021 ◽

2011 ◽

Vol 77 (10) ◽

pp. 1364-1367 ◽

Cited By ~ 5

Author(s):

Jenny J. Lee ◽

Jeannie Shen

Keyword(s):

Estrogen Receptor ◽

Clinical Utility ◽

Recurrence Score ◽

Distant Recurrence ◽

Good Prognosis ◽

Oncotype Dx ◽

Breast Cancers ◽

Hospital Patients ◽

Estrogen Receptor Positive ◽

Er Positive

The 21-gene Oncotype DX recurrence score (RS) assay quantifies risk of distant recurrence and predicts benefit from chemotherapy in tamoxifen-treated estrogen receptor (ER)-positive, node-negative breast cancer. Although clinically useful, the assay costs roughly $4650. Because the assay is weighted heavily towards expression of ER, our objective was to determine its clinical utility in strongly ER-positive tumors. This was a retrospective study of Huntington Hospital patients undergoing an Oncotype DX assay between 2007 and 2010. Data collected included patient age, expression of ER, progesterone receptor (PR), HER2/neu, ki67, and p53, tumor size, node status, lymphovascular invasion, and nuclear grade. Of 133 total patients, 84 (63.2%) had strongly ER-positive tumors (≥90% expression). Only seven of 84 patients (8.3%) had a high risk RS (>30), indicating statistically significant predicted benefit from chemotherapy. All seven had intermediate to high ki67 expression (>20%) and lower PR expression (≤50%). Our study demonstrates that the clinical utility of the Oncotype DX assay in these patients is limited as most patients with strongly ER-positive tumors will have a low or intermediate RS. Future studies are needed to identify additional predictive factors in these patients with otherwise good prognosis.

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ZMIZ1 — A novel Estrogen Receptor co-activator that enhances the growth of ER+ breast cancer

10.1101/789610 ◽

2019 ◽

Author(s):

Anže Godicelj ◽

Ryan Blake ◽

Federico M Giorgi ◽

Marcel Gehrung ◽

Sanjeev Kumar ◽

...

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Protein Interactions ◽

Quantitative Proteomics ◽

Breast Cancers ◽

Rna Seq ◽

Protein Protein Interactions ◽

Cell Cycle Genes ◽

Genome Wide ◽

Er Positive

AbstractThe Estrogen Receptor (ER) drives 75% of breast cancers. On activation, the ER recruits specific co-factors to form a transcriptionally active complex. These co-factors can modulate tumour growth and understanding their roles can help to identify new therapeutic targets.We applied a quantitative proteomics method, qPLEX-RIME, to analyse the ER protein complex and characterise changes in protein-protein interactions on activation. Our analysis identified ZMIZ1 as novel co-factor within the ER chromatin-bound complex, extending its known role as a co-factor of the Androgen Receptor. We find further evidence for an ER–ZMIZ1 interaction by showing that both proteins are co-expressed in biopsy samples. We characterise ZMIZ1 function by showing that targeting ZMIZ1 results in the reduction of ER transcriptional activity and significantly reduces the proliferation of ER-positive cell lines. We validated these results genome-wide by RNA-seq and identified that targeting ZMIZ1 resulted in a specific reduction of estradiol-induced cell cycle genes.These results establish ZMIZ1 as a having a key role in the ability of the ER to activate key genes that drive the proliferation of breast cancer, and its biological importance in patient tumours.

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Tamoxifen resistance alters sensitivity to 5-fluorouracil in a subset of estrogen receptor-positive breast cancer

PLoS ONE ◽

10.1371/journal.pone.0252822 ◽

2021 ◽

Vol 16 (6) ◽

pp. e0252822

Author(s):

Takayuki Watanabe ◽

Takaaki Oba ◽

Keiji Tanimoto ◽

Tomohiro Shibata ◽

Shinobu Kamijo ◽

...

Keyword(s):

Breast Cancer ◽

T Cells ◽

Estrogen Receptor ◽

Endocrine Therapy ◽

Chemotherapeutic Agents ◽

Breast Cancers ◽

Mcf7 Cells ◽

Er Positive ◽

Tamoxifen Resistant ◽

Positive Breast Cancer

Sequential treatment with endocrine or chemotherapy is generally used in the treatment of estrogen receptor (ER)-positive recurrent breast cancer. To date, few studies have investigated the effect of long-term endocrine therapy on the response to subsequent chemotherapy in ER-positive breast cancer. We examined whether a preceding endocrine therapy affects the sensitivity to subsequent chemotherapy in ER-positive breast cancer cells. Three ER-positive breast cancer cell lines (T47D, MCF7, BT474) and tamoxifen-resistant sublines (T47D/T, MCF7/T, BT474/T) were analyzed for sensitivity to 5-fluorouracil, paclitaxel, and doxorubicin. The mRNA levels of factors related to drug sensitivity were analyzed by RT-PCR. MCF7/T cells became more sensitive to 5-fluorouracil than wild-type (wt)-MCF7 cells. In addition, the apoptosis induced by 5-fluorouracil was significantly increased in MCF7/T cells. However, no difference in sensitivity to chemotherapeutic agents was observed in T47D/T and BT474/T cells compared with their wt cells. Dihydropyrimidine dehydrogenase (DPYD) mRNA expression was significantly decreased in MCF7/T cells compared with wt-MCF7 cells. The expression of DPYD mRNA was restored with 5-azacytidine treatment in MCF7/T cells. In addition, DPYD 3′-UTR luciferase activity was significantly reduced in MCF7/T cells. These data indicated that the expression of DPYD mRNA was repressed by methylation of the DPYD promoter region and post-transcriptional regulation by miRNA in MCF7/T cells. In the mouse xenograft model, capecitabine significantly reduced the tumor volume in MCF7/T compared with MCF7. The results of this study indicate that endocrine therapy could alter the sensitivity to chemotherapeutic agents in a subset of breast cancers, and 5-fluorouracil may be effective in tamoxifen-resistant breast cancers.

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Basal subtype and clinical estrogen receptor status of genomically basal breast tumors in Caucasian, African American, and Latin American patients.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.556 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 556-556

Author(s):

Virginia G. Kaklamani ◽

Cathy Graham ◽

Karen L. Tedesco ◽

Abirami Sivapiragasam ◽

Jennifer A. Crozier ◽

...

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Latin American ◽

Triple Negative ◽

Breast Tumors ◽

Gene Signature ◽

Receptor Expression ◽

Exact Test ◽

Er Positive ◽

Basal Type

556 Background: Genomically basal-type breast cancer is a heterogenous subtype that occurs at higher frequencies in non-Caucasian patients. Triple negative breast cancer (TNBC) has been refined into distinct transcriptomic groups including the basal-like immunoactive (BLIA), basal-like immunosuppressed (BLIS), luminal androgen receptor (LAR), and mesenchymal (MES) subtypes. Here we report the distribution of triple negative subtypes in genomically basal cancers from Caucasian (CA), African American (AA), and Latin American (LA) patients and the association of clinical estrogen receptor (ER) status. Methods: The FLEX Registry (NCT03053193) is an ongoing, prospective study evaluating primary tumors from patients with stage I-III breast cancer who receive the 70-gene signature and 80-gene signature (80-GS) molecular testing and consent to clinically annotated full transcriptome data collection. This sub-analysis evaluated 143 80-GS Basal type tumors from patients with self-reported ethnicity (60 CA, 59 AA, 24 LA). TNBC subtypes BLIA, BLIS, LAR, and MES were derived using an adjusted version of the 80-gene centroid signature published by Burstein and colleagues (2015). Differences in clinical ER expression between ethnicities were assessed by Fisher’s exact test. Results: Basal indices from 80-GS were not influenced by patient ethnicity (one-way ANOVA, p = 0.182). The frequency of BLIA, BLIS, LAR, and MES subtypes did not vary significantly by ethnicity (Fisher’s exact test, p = 0.671). The majority of tumors in all ethnic groups were BLIS (67% CA, 75% AA, 63% LA), followed by BLIA (22% CA, 22% AA, 25% LA), with low frequency of LAR (5% CA, 1.7% AA, 8.3% LA) and MES (5% CA, 1.7% AA, 4.2% LA) subtypes. Nearly one third (31%) of Basal type tumors were defined by IHC as ER positive and were present in all TNBC subtypes (39% BLIA, 29% BLIS, 33% LAR, and 20% MES); ER receptor expression ranged from 1-90% and was not associated with specific basal subtype (p = 0.8) nor ethnicity (P = 0.76). Progesterone receptor expression ranged from 1-50%. Conclusions: This analysis demonstrated that genomic Basal type tumor classification by 80-GS encompasses all TNBC subtypes evaluated regardless of ethnicity. Additionally, we show that IHC ER positive tumors occur in all TNBC subtypes assessed. These findings confirm the heterogeneous nature of basal breast tumors in CA, AA, and LA patients and highlight the clinical need to delineate basal biology in the ER+ cohort to advance treatment for basal-like tumors. Clinical trial information: NCT03053193 .

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