Breast cancer chemoprevention

Trials with tamoxifen have clearly shown that the risk of developing oestrogen receptor positive breast cancer can be reduced by at least 50% with prophylactic agents. The current challenge is to find new agents which achieve this or better efficacy, but with fewer side effects. Recent results indicate that the SERM raloxifene has similar efficacy to tamoxifen, but leads to fewer endometrial cancers, gynecological symptoms, and thromboembolic events. Results for contralateral tumors in adjuvant trials suggest that aromatase inhibitors may be able to prevent up to 70%–80% of ER-positive breast cancers, and this is currently being investigated in two large prevention trials, one using anastrozole (IBIS-II) and the other exemestane (MAP.3). New agents are needed for receptor negative breast cancer and several possibilities are currently under investigation.

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Breast cancer chemoprevention

Oncology Reviews ◽

10.4081/oncol.2008.130 ◽

2011 ◽

pp. 223-228

Author(s):

Ivana Sestak ◽

Jack Cuzick

Keyword(s):

Breast Cancer ◽

Cancer Chemoprevention ◽

Similar Efficacy ◽

Breast Cancers ◽

New Agents ◽

Breast Cancer Chemoprevention ◽

Er Positive ◽

Prevention Trials ◽

Endometrial Cancers ◽

Positive Breast Cancer

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

Journal of Clinical Oncology ◽

10.1200/jco.2009.23.9616 ◽

2010 ◽

Vol 28 (7) ◽

pp. 1161-1167 ◽

Cited By ~ 75

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.

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Immune Checkpoint Profiles in Luminal B Breast Cancer (Alliance)

JNCI Journal of the National Cancer Institute ◽

10.1093/jnci/djz213 ◽

2019 ◽

Vol 112 (7) ◽

pp. 737-746 ◽

Cited By ~ 9

Author(s):

Meenakshi Anurag ◽

Mayanne Zhu ◽

Chen Huang ◽

Suhas Vasaikar ◽

Junkai Wang ◽

...

Keyword(s):

Breast Cancer ◽

Tissue Microarray ◽

Microarray Analysis ◽

Immune Tolerance ◽

Immune Checkpoint ◽

Mrna Levels ◽

Breast Cancers ◽

Er Positive ◽

Tissue Microarray Analysis ◽

Positive Breast Cancer

Abstract Background Unlike estrogen receptor (ER)-negative breast cancer, ER-positive breast cancer outcome is less influenced by lymphocyte content, indicating the presence of immune tolerance mechanisms that may be specific to this disease subset. Methods A supervised analysis of microarray data from the ACOSOG Z1031 (Alliance) neoadjuvant aromatase inhibitor (AI) trial identified upregulated genes in Luminal (Lum) B breast cancers that correlated with AI-resistant tumor proliferation (percentage of Ki67-positive cancer nuclei, Pearson r > 0.4) (33 cases Ki67 > 10% on AI) vs LumB breast cancers that were more AI sensitive (33 cases Ki67 < 10% on AI). Overrepresentation analysis was performed using WebGestalt. All statistical tests were two-sided. Results Thirty candidate genes positively correlated (r ≥ 0.4) with AI-resistant proliferation in LumB and were upregulated greater than twofold. Gene ontologies identified that the targetable immune checkpoint (IC) components IDO1, LAG3, and PD1 were overrepresented resistance candidates (P ≤ .001). High IDO1 mRNA was associated with poor prognosis in LumB disease (Molecular Taxonomy of Breast Cancer International Consortium, hazard ratio = 1.43, 95% confidence interval = 1.04 to 1.98, P = .03). IDO1 also statistically significantly correlated with STAT1 at protein level in LumB disease (Pearson r = 0.74). As a composite immune tolerance signature, expression of IFN-γ/STAT1 pathway components was associated with higher baseline Ki67, lower estrogen, and progesterone receptor mRNA levels and worse disease-specific survival (P = .002). In a tissue microarray analysis, IDO1 was observed in stromal cells and tumor-associated macrophages, with a higher incidence in LumB cases. Furthermore, IDO1 expression was associated with a macrophage mRNA signature (M1 by CIBERSORT Pearson r = 0.62 ) and by tissue microarray analysis. Conclusions Targetable IC components are upregulated in the majority of endocrine therapy–resistant LumB cases. Our findings provide rationale for IC inhibition in poor-outcome ER-positive breast cancer.

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ER-Negative Breast Cancer Is Highly Responsive to Cholesterol Metabolite Signalling

Nutrients ◽

10.3390/nu11112618 ◽

2019 ◽

Vol 11 (11) ◽

pp. 2618 ◽

Cited By ~ 4

Author(s):

Samantha A Hutchinson ◽

Priscilia Lianto ◽

Hanne Roberg-Larsen ◽

Sebastiano Battaglia ◽

Thomas A Hughes ◽

...

Keyword(s):

Breast Cancer ◽

Cell Lines ◽

Target Genes ◽

Cholesterol Metabolism ◽

Breast Cancers ◽

Breast Cancer Patients ◽

Cancer Subtypes ◽

Hormone Receptor Positive ◽

Er Positive ◽

Positive Breast Cancer

Interventions that alter cholesterol have differential impacts on hormone receptor positive- and negative-breast cancer risk and prognosis. This implies differential regulation or response to cholesterol within different breast cancer subtypes. We evaluated differences in side-chain hydroxycholesterol and liver X nuclear receptor signalling between Oestrogen Receptor (ER)-positive and ER-negative breast cancers and cell lines. Cell line models of ER-positive and ER-negative disease were treated with Liver X Receptor (LXR) ligands and transcriptional activity assessed using luciferase reporters, qPCR and MTT. Publicly available datasets were mined to identify differences between ER-negative and ER-positive tumours and siRNA was used to suppress candidate regulators. Compared to ER-positive breast cancer, ER-negative breast cancer cells were highly responsive to LXR agonists. In primary disease and cell lines LXRA expression was strongly correlated with its target genes in ER-negative but not ER-positive disease. Expression of LXR’s corepressors (NCOR1, NCOR2 and LCOR) was significantly higher in ER-positive disease relative to ER-negative, and their knock-down equalized sensitivity to ligand between subtypes in reporter, gene expression and viability assays. Our data support further evaluation of dietary and pharmacological targeting of cholesterol metabolism as an adjunct to existing therapies for ER-negative and ER-positive breast cancer patients.

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Update of the Oxford Overview: New Insight and Perspectives in the Era of Personalized Medicine

American Society of Clinical Oncology Educational Book ◽

10.14694/edbook_am.2012.32.199 ◽

2012 ◽

pp. 71-79

Author(s):

Kathleen I. Pritchard ◽

Jonas Bergh ◽

Harold J. Burstein

Keyword(s):

Breast Cancer ◽

Hormone Receptor ◽

Meta Analysis ◽

Breast Cancers ◽

Breast Cancer Therapy ◽

Hormone Receptor Positive ◽

Er Positive ◽

Adjuvant Breast Cancer ◽

Great Appreciation ◽

Positive Breast Cancer

Overview: There is great appreciation for the heterogeneity of breast cancers, particularly of hormone-receptor positive breast cancers. A goal of modern oncology managing such heterogeneity is to determine how to individualize therapy based on the specific pathological and biological features of a given tumor. Two distinctive clinical literatures exist to guide treatment of hormone-receptor-positive breast cancer. The Oxford Overview, a seminal meta-analysis effort, has recently been updated, and suggests that nearly all patients with ER-positive tumors benefit from adjuvant endocrine therapy. In addition, the overview finds that nearly all subsets of patients with ER-positive tumors also benefit from modern adjuvant chemotherapy regimens. Meanwhile, retrospective subset analyses of specific trials or populations suggests that the benefits of chemotherapy are not so uniform, and in particular that molecular diagnostics assays can identify patients who do not warrant chemotherapy. This article will highlight recent data and controversies in personalizing adjuvant breast cancer therapy.

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Is obesity associated with increased recurrence risk in estrogen receptor (ER)-positive breast cancer?

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.27_suppl.171 ◽

2011 ◽

Vol 29 (27_suppl) ◽

pp. 171-171 ◽

Cited By ~ 1

Author(s):

K. K. L. Yap ◽

D. N. Efiom-Ekaha

Keyword(s):

Breast Cancer ◽

Weight Gain ◽

Pearson Correlation ◽

Cancer Recurrence ◽

Oncotype Dx ◽

Breast Cancer Recurrence ◽

Breast Cancers ◽

Obese Women ◽

Er Positive ◽

Positive Breast Cancer

171 Background: Oncotype DX Score is a 21-gene expression analysis that has been validated clinically as a reliable predictor of breast cancer recurrence for ER-positive, node-negative breast cancers. Obesity is recognized as a risk factor for many cancers, including breast cancer. Additionally obesity has been shown to be an independent prognostic factor in breast cancer. The primary objective of this study is to determine the correlation between obesity and Oncotype DX score, hence the relationship between obesity and breast cancer recurrence in ER-positive breast cancer. The secondary objective is to investigate the association between weight gain after diagnosis and breast cancer recurrence. Methods: An IRB-exempted retrospective chart review of female patients at Wellspan Group with ER-positive breast cancer who had Oncotype DX analysis in 2008 and 2009. Data collected included Oncotype DX score and BMI (at diagnosis, 6 months and 12 months). Data were analyzed to determine the correlation between Oncotype DX score and BMI at diagnosis, at 6 months and at 12 months. The correlation between Oncotype DX score and BMI changes at 12 months also was determined. Results: A total of 125 patients were identified; 103 had BMI recorded at diagnosis, 88 had BMI recorded at 6 months and 87 had BMI recorded at 12 months. Of these, we were able to determine the BMI changes at 12 months for 82 patients. The Pearson correlation scores were 0.091 (p = 0.361), 0.074 (p = 0.492), and 0.047 (p = 0.669) for BMI at diagnosis, at 6 months and at 12 months respectively. The Pearson correlation score was 0.007 (p = 0.948) for BMI changes at 12 months. Conclusions: Obesity and weight gain are not independent predictors of recurrence in patients with ER-positive breast cancer. The reported adverse prognostic associations may be more prominent in ER-negative breast cancers. This is consistent with the reports suggesting a higher rate of ER-negative, high-grade cancers in obese women as well as a greater magnitude of benefit from dietary and weight reduction interventions seen in women with ER-negative cancers.

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Narciclasine Targets STAT3 via Distinct Mechanisms in Tamoxifen-Resistant Breast Cancer Cells

10.21203/rs.3.rs-680769/v1 ◽

2021 ◽

Author(s):

Chao Lv ◽

Yun Huang ◽

Rui Huang ◽

Qun Wang ◽

Hongwei Zhang ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Sh2 Domain ◽

Breast Cancers ◽

Stat3 Phosphorylation ◽

Er Positive ◽

Tamoxifen Resistant ◽

Mcf 7 ◽

Positive Breast Cancer

Abstract Background: Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in multiple malignant tumors. Compared with regular estrogen receptor (ER)-positive breast cancers, the patients with tamoxifen-resistant breast cancers often exhibit higher level of STAT3 phosphorylation. Narciclasine (Nar) possesses strong inhibiting effects against a variety of cancer cells, however, the underlying antitumor target(s)/mechanism(s) remains barely understood. Methods: Targets prediction of narciclasine was performed by combining connectivity map (CMAP) and drug affinity responsive target stability (DARTS) strategy. Molecular and biochemical methods were used to elucidate the distinct mechanisms of narciclasine targeting STAT3. The narciclasine nano-delivery system was synthesized by thin film hydration method. Xenograft models were established to determine antitumor activity of narciclasine and its liposome in vivo.Results: In this study, we successfully identified the STAT3 was the direct target of Nar through the combination strategies of CMAP and DARTS. In ER-positive breast cancer cells, Nar could suppress phosphorylation, activation, dimerization, and nuclear translocation of STAT3 by directly binding with the STAT3 SH2 domain. Additionally, Nar could also specifically promote total STAT3 degradation via proteasome pathway and reduce the STAT3 protein stability in tamoxifen-resistant breast cancer cells (MCF-7/TR). This distinct mechanism of Nar targeting STAT3 was mainly attributed to the various levels of reactive oxygen species (ROS) in regular and tamoxifen-resistant ER-positive breast cancer cells. Meanwhile, Nar loaded nanoparticles could markedly decrease the protein levels of STAT3 in tumor sites, resulting in significant MCF-7/TR xenograft tumor regression without obvious toxicity. Conclusions: Our findings successfully highlight the STAT3 as the direct therapeutic target of Nar in ER-positive breast cancer cells, especially Nar leaded STAT3 degradation as a promising strategy for the tamoxifen-resistant breast cancer treatment.

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miR10a Mediate Tamoxifen Resistance in ER-Positive Breast Cancer Cells Through Down-Regulation of RFPL-3/hTERT

10.21203/rs.3.rs-819836/v1 ◽

2021 ◽

Author(s):

Wei Sun ◽

Wenjie Han ◽

Aiying Li ◽

Youkui Shi

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Tamoxifen Resistance ◽

Negative Regulator ◽

Luciferase Reporter ◽

Endocrine Treatment ◽

Breast Cancers ◽

Er Positive ◽

Positive Breast Cancer

Abstract Tamoxifen (TAM) is used as a first-line endocrine treatment for estrogen receptor (ER)-positive breast cancers. However, some patients develop TAM resistance after treatment and the role of miRNAs in TAM resistance still unknown. qPCR assay was performed to assess the expression levels of miR10a and RFPL-3 /hTERT. Western blot analysis was used to determine RFPL-3 /hTERT levels. The direct correlation between miR10a and RFPL-3 was verified by dual-luciferase reporter assay. CCK-8 assay and PicoGreen dsDNA quantification assay were applied to determine cell proliferation ability. In this study, we found that miR10a is downregulated in breast cancer with TAM resistance and that low expression of miR10a is associated with poor prognosis. By studying the regulatory mechanism, we found that miR10a functions as a negative regulator of RFPL-3 mRNA by binding the 3’-UTR region and disrupting the interaction between RFPL-3 and hTERT, which inhibits the proliferation of ER-positive breast cancer cells with TAM resistance. Collectively, our study findings indicate that the downregulation of miR10a activates RFPL-3/hTERT and induces tamoxifen resistance in ER-positive breast cancer cells.

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Progress in breast cancer chemoprevention.

Endocrine Related Cancer ◽

10.1677/erc.0.0090015 ◽

2002 ◽

pp. 15-32 ◽

Cited By ~ 12

Author(s):

B Arun ◽

G N Hortobagyi

Keyword(s):

Breast Cancer ◽

New Technologies ◽

Cancer Chemoprevention ◽

Chemopreventive Agents ◽

The Past ◽

Breast Cancer Chemoprevention ◽

Clinical Breast ◽

Prevention Trials ◽

First Time ◽

Made In

Over the past years there have been significant advances in breast cancer treatment and early detection. For the first time, a decrease in cancer mortality has been observed. Recently, much progress has been made in the understanding of carcinogenesis partly due to available new technologies to detect early molecular changes in the tissue. The knowledge of breast cancer carcinogenesis has provided possible opportunities to prevent breast cancer. Currently, several clinical breast cancer prevention trials are ongoing. This paper reviews issues related to breast cancer chemoprevention including identification of high risk cohorts, endpoint biomarkers, current and new chemopreventive agents as well as models to evaluate these agents.

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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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