Endocrine Response In Breast Cancer Research Articles

Breast Cancer-Stromal Interactions: Adipose-Derived Stromal/Stem Cell Age and Cancer Subtype Mediated Remodeling.

Adipose tissue is characterized as an endocrine organ that acts as a source of hormones and paracrine factors. In diseases such as cancer, endocrine and paracrine signals from adipose tissue contribute to cancer progression. Young individuals with estrogen receptor-alpha positive (ER-α+) breast cancer (BC) have an increased resistance to endocrine therapies, suggesting that alternative estrogen signaling is activated within these cells. Despite this, the effects of stromal age on the endocrine response in BC are not well defined. To identify differences between young and aged ER-α+ breast tumors, RNA sequencing data were obtained from The Cancer Genome Atlas. Analysis revealed enrichment of matrix and paracrine factors in young (≤40 years old) patients compared to aged (≥65 years old) tumor samples. Adipose-derived stromal/stem cells (ASCs) from noncancerous lipoaspirate of young and aged donors were evaluated for alterations in matrix production and paracrine secreted factors to determine if the tumor stroma could alter estrogen signaling. Young and aged ASCs demonstrated comparable proliferation, differentiation, and matrix production, but exhibited differences in the expression levels of inflammatory cytokines (Interferon gamma, interleukin [IL]-8, IL-10, Tumor necrosis factor alpha, IL-2, and IL-6). Conditioned media (CM)-based experiments showed that young ASC donor age elevated endocrine response in ER-α+ BC cell lines. MCF-7 ER-α+ BC cell line treated with secreted factors from young ASCs had enhanced ER-α regulated genes (PGR and SDF-1) compared to MCF-7 cells treated with aged ASC CM. Western blot analysis demonstrated increased activation levels of p-ER ser-167 in the MCF-7 cell line treated with young ASC secreted factors. To determine if ER-α+ BC cells heightened the cytokine release in ASCs, ASCs were stimulated with MCF-7-derived CM. Results demonstrated no change in growth factors or cytokines when treated with the ER-α+ secretome. In contrast to ER-α+ CM, the ER-α negative MDA-MB-231 derived CM demonstrated increased stimulation of pro-inflammatory cytokines in ASCs. While there was no observed change in the release of selected paracrine factors, MCF-7 cells did induce matrix production and a pro-adipogenic lineage commitment. The adipogenesis was evident by increased collagen content through Sirius Red/Fast Green Collagen stain, lipid accumulation evident by Oil Red O stain, and significantly increased expression in PPARγ mRNA expression. The data from this study provide evidence suggesting more of a subtype-dependent than an age-dependent difference in stromal response to BC, suggesting that this signaling is not heightened by reciprocal signals from ER-α+ BC cell lines. These results are important in understanding the mechanisms of estrogen signaling and the dynamic and reciprocal nature of cancer cell-stromal cell crosstalk that can lead to tumor heterogeneity and variance in response to therapy.

Predictive markers of endocrine response in breast cancer

Ongoing clinical and research efforts seek to optimise the use of endocrine therapy in the treatment of breast cancer. Accurate biomarkers are needed that predict response for individual patients. The presence of the estrogen receptor (ER) as the direct (for tamoxifen and fulvestrant) or indirect (for aromatase inhibitors) target molecule for endocrine therapy remains the foremost biomarker and determinant of response. However, ER expression only poorly predicts outcome and further indicators of response or resistance are required. The development and application of molecular signature assays such as Oncotype Dx, Prosigna, Mammaprint and Endopredict have provided valuable information on prognosis and these are being used to support clinical decision making on whether endocrine therapy alone alongside surgery is sufficient for ER-positive early stage breast cancers or whether combination of endocrine with chemotherapy are also warranted. Ki67, the proliferation marker, has been widely used in the neo-adjuvant (pre-operative) setting to help predict response and long term outcome. Gene expression studies within the same setting have allowed monitoring of changes of potential predictive markers. These have identified frequent changes in estrogen-regulated and proliferation genes. Specific molecules such as mutant ER may also prove helpful biomarkers in predicting outcome and monitoring response to treatment.

Abstract 1258: The unfolded protein response may contribute to racial disparity in endocrine responsiveness in breast cancer

Abstract About 70% of all breast cancers are estrogen receptor alpha positive (ER+) and depend on estrogen to grow and proliferate. Anti-hormone therapy such as antiestrogens (e.g., Tamoxifen; TAM) are often used to treat ER+ breast tumors but the cancer cells can develop resistance to these drugs (endocrine resistance). Unfortunately, ∼50% percent of all antiestrogen treated tumors eventually develop endocrine resistance, and therefore, there is an urgent need to find ways to treat this incurable disease. Nonetheless, little is known about the causes of endocrine resistance, and even less is known about the racial disparities that exist for antiestrogen responsiveness among ER+ breast cancer cases. Clinical investigations into ER+ breast cancer cases with similarly treated tumors showed that progression-free survival (PFS) and overall survival (OS) in African-American (AA) women were worse than in European-American (EA) women. The underlying causes of these racial differences within ER+ breast cancers is unknown. One cellular adaptive mechanism that allow endocrine resistant cells to survive antiestrogen treatment is a called the unfolded protein response (UPR) that is initiated within the endoplasmic reticulum caused by a stress stimulus. Cellular stress induced by antiestrogens can trigger the UPR leading to induce a pro-survival response by inhibiting cell death (by apoptosis) and promoting cell survival (by autophagy). Gene expression analysis for ER+ tumors of AA patients show up-regulation of UPR genes such as glucose-regulated protein 78, GRP78 (also known as HSP5A or BiP), activation transcription factor-6 (ATF6) and spliced X-box-protein-1 (XBP1s). Moreover, ER+ breast cancer cell lines derived from tumors of AA patients show increased levels of GRP78, ATF6 and XBP1 compared with cells derived from EA patients. The ER+ breast cancer cell lines derived from tumors of AA patients also show reduced sensitivity to Tamoxifen compared with cells derived from EA patients. Through our study, we will determine how up-regulation of the UPR contribute to the differences noted in anti-hormone therapy in treatment of ER+ breast cancer in AA versus EA women. Therefore, targeting critical pro-survival signaling molecules of the UPR can inhibit endocrine resistance and reduce growth of ER+ breast cancer cells more efficiently and avoid unsuccessful treatment in AA breast cancer patients. Citation Format: Ahreej E. Eltayeb, Diane M. Demas, Robert Clarke, Ayesha N. Shajahan-Haq. The unfolded protein response may contribute to racial disparity in endocrine responsiveness in breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1258. doi:10.1158/1538-7445.AM2015-1258

DNA methylation of oestrogen-regulated enhancers defines endocrine sensitivity in breast cancer.

Expression of oestrogen receptor (ESR1) determines whether a breast cancer patient receives endocrine therapy, but does not guarantee patient response. The molecular factors that define endocrine response in ESR1-positive breast cancer patients remain poorly understood. Here we characterize the DNA methylome of endocrine sensitivity and demonstrate the potential impact of differential DNA methylation on endocrine response in breast cancer. We show that DNA hypermethylation occurs predominantly at oestrogen-responsive enhancers and is associated with reduced ESR1 binding and decreased gene expression of key regulators of ESR1 activity, thus providing a novel mechanism by which endocrine response is abated in ESR1-positive breast cancers. Conversely, we delineate that ESR1-responsive enhancer hypomethylation is critical in transition from normal mammary epithelial cells to endocrine-responsive ESR1-positive cancer. Cumulatively, these novel insights highlight the potential of ESR1-responsive enhancer methylation to both predict ESR1-positive disease and stratify ESR1-positive breast cancer patients as responders to endocrine therapy.

Chromatin Landscape and Endocrine Response in Breast Cancer

Over two-thirds of breast cancers rely on estrogen receptor α (ERα) for their growth. Endocrine therapies antagonize estrogen-dependent ERα activation but resistance to these treatments occurs and is associated with poor prognosis. Crosstalk between alternative survival pathways and ERα are currently held as the primary cause of resistance. However, blocking these pathways does not cure endocrine therapy resistant breast cancer suggesting the existence of additional mechanisms. While cancer is commonly considered a genetic disease, the importance of epigenetic events in promoting tumor initiation and progression is increasingly recognized. Here, we consider how epigenetic modifications and alterations to the chromatin landscape contribute to endocrine therapy resistance by modulating ERα expression or altering its genomic activity.

Lost in Translation? Estrogen Receptor Status and Endocrine Responsiveness in Breast Cancer

this editorial and elsewhere 2-4,12,14 testify to the long arc of hormone receptor‐positive breast cancer, confirm the enduring overall safety of tamoxifen and AIs, and provide reassurance that the well-characterized major adverse events of therapy either stabilize or resolve with cessation of treatment. The substantial near-term successes of adjuvant chemotherapy and endocrine therapy have shifted both the natural history and the dialogue in ER-positive, early-stage breast cancer for oncologists and patients alike. The issue of late recurrence—deep time for clinicians and survivors— has emerged as a fundamental challenge. RCTs have shown equivalence for either 5 years of AI treatment or a sequenced regimen of tamoxifen followed by an AI for a total of 5 years. 13,18 For women who receive AI-based adjuvant treatment, it remains unclear whether a longer program of extended therapy with an AI beyond 5 years of initial adjuvant treatment will outperform a shorter 5-year course of adjuvant endocrine therapy. Progress in the deep time problem of early-stage breast cancer will depend on answering the long and the short of that question.

Relationship between single nucleotide polymorphism of estrogen receptor gene and endocrine therapy efficacy in breast cancer

1113 Objective: To explore the distribution of single nucleotide polymorphism (SNP) loci of estrogen receptor (ESR1) gene in breast cancer patients and to study the relationship between the SNP genotypes and the efficacy to endocrine therapy. Methods: Fifteen SNP loci ( rs872921 , rs2077647, rs3904766, rs2234693, rs11155816, rs827419 , rs2347867, rs3798759, rs1801132, rs985191 , rs9340931, rs9397463, rs722209 , rs3778099, and rs3798577) of ESR1 gene were selected as genetic markers. PCR-restriction fragment length polymorphisms, PCR-DNA sequencing and allele-specific real time PCR methods were employed to analyze the loci genotype of 240 patients with breast cancer accepted endocrine therapy. Results: The loci rs872921 and rs3904766 were abandoned for poor ploymorphisms, and the other 13 loci had polymorphisms. The frequencies of alleles and genotypes of rs2077647 and rs3798759 were significantly related with the efficacy of endocrine therapy (p < 0. 05). The linkage disequilibrium and the hapotype analysis showed that there were four linkage disequilibrium blocks in ESR1 gene. They were rs2077647∼rs2234693 (LD1), rs2234693∼rs11155816 (LD2), rs9397463∼ rs722209 (LD3), and rs3778099∼rs3798577 (LD4), and the hapotypes of LD2, LD3, s11155816- rs827419 , and rs2347867- rs1801132 were positively related with the efficacy of endocrine therapy (p < 0. 05). Conclusions: Some of the polymorphisms of ESR1 gene and the haplotypes are positively associated with the endocrine therapy efficacy, and maybe account for predicting the endocrine response in breast cancer. No significant financial relationships to disclose.

Vasomotor or joint symptoms as a marker of endocrine response in breast cancer

Vasomotor or joint symptoms as a marker of endocrine response in breast cancer

Prognostic effect of estrogen receptor status across age in primary breast cancer

Estrogen receptor (ER) status is considered as an important prognostic factor as well as a predictive factor for endocrine responsiveness in breast cancer. We analyzed the distribution of ER status across age and estimated variations in the prognostic impact of ER status related to patients' age and time since diagnosis. Overall, 26,944 patients with primary breast cancer diagnosed from 1989 to 2004 were included. The proportion of ER positive tumors increased over age from 51 to 82%. In multivariate analysis of overall survival, ER positive status was found to be a significantly positive prognostic factor over all age groups. This effect was limited to the first 5 years after diagnosis, RR: 2.08 (95% CI: 1.95-2.22, p < 0.0001). Overall survival during the following 5 years was slightly superior for women with ER negative tumors, RR of death: 0.89 (95% CI: 0.79-1.00, p = 0.049). Results were unchanged in patients who did not receive adjuvant systemic therapy (n = 6,272). Thus, positive ER status does not confer a negative impact on survival in young women as has been previously reported. The inferior prognosis for ER negative patients during the first 5 years after diagnosis changes into a slightly superior residual prognosis compared to ER positive patients independent of use of adjuvant systemic therapy. This may have an impact on future designing of guidelines for adjuvant endocrine therapy beyond 5 years.

S33 Benefit with adjuvant taxanes and endocrine responsiveness in breast cancer (BC)

S33 Benefit with adjuvant taxanes and endocrine responsiveness in breast cancer (BC)

Benefit from adjuvant taxanes and endocrine responsiveness in breast cancer

Several phase III trials have been coincident in showing a benefit with adjuvant taxanes in node-positive breast cancer (BC). These trials provide level I evidence of the efficacy of these drugs. The absolute 5-year DFS gain obtained with the taxane-containing regimens in the positive studies ranged from 4% to 7%. However, the regimens including taxanes are more toxic than the conventional anthracyline-containing combinations. Therefore, the pre-treatment identification of the small proportion of patients who actually benefit from taxanes is of major importance. Several attempts have been made to identify the biological peculiarities of the BC patients who benefit most with taxanes, largely based on retrospective subset analyses. Hormone receptor (HR) status, one of the critical determinants of BC biology, had been suggested to be a factor modulating response to adjuvant chemotherapy in general and taxanes in particular. Unfortunately, none of the first-generation adjuvant taxane trials was designed to address the question of the differential efficacy of taxanes in the specific subgroups of HR positive and HR negative BC patients. Indirect (retrospective, unplanned) analysis suggest that the magnitude of benefit from taxanes is somewhat more in the HR negative subset, but the benefit also exists, and is clinically relevant, in patients with HR positive cancers. Therefore, the predictive value of HR status in the selection of patients for adjuvant taxane therapy is low. The predictive value of HER2 status in addition to HR status to select patients for the same purpose remains controversial.

Impact of altered growth factor signalling on endocrine response in breast cancer and the transition from ER+ to ER− disease

This article examines the experimental and clinical evidence of the effect of growth factor signalling in an attempt to reconcile the seeming paradox of, on the one hand, evidence that growth factor signalling can facilitate the activity of oestrogen receptor-α (ER-α), and on the other hand, evidence that extreme growth factor signalling can promote loss of ER function and expression, thereby promoting an endocrine insensitive and ultimately ER− phenotype. The results of this analysis lead to the therapeutic possibility that ER negativity may, in some instances, be reversible to generate endocrine response and improve patient prognosis.

Involvement of steroid hormone and growth factor cross-talk in endocrine response in breast cancer.

Multiple lines of evidence implicate steroid hormone and growth factor cross-talk as a modulator of endocrine response in breast cancer and that aberrations in growth factor signaling pathways are a common element in the endocrine resistant phenotype. Delineation of these relationships is thus an important diagnostic goal in cancer research, while the targeting of aberrant growth factor signaling holds the promise of improving therapeutic response rates.

P21(WAF1) expression and endocrine response in breast cancer.

An immunocytochemical assay for the p53-regulated protein product of the WAF1/Cip1 gene, p21(WAF1) (p21), was developed and applied to archival primary breast tumour material from 91 patients whose subsequent recurrent disease was treated with assessable courses of endocrine therapy. Nuclear localization of p21 protein was observed in 76 (82.4 per cent) cases. Status cut-offs were established and 29 (31.9 per cent) were deemed negative, 39 (42.9 per cent) weakly positive, and 23 (25.3 per cent) strongly positive. p21 status was inversely correlated with p53 protein (p=0.047) but did not relate to oestrogen receptor (ER) status, response to endocrine therapy, or time to further disease progression (TTP). Highly p21-positive patients had a significantly improved overall survival time (p=0. 020). Co-assessment of p21 and p53 subgroups revealed p21+/p53- patients to have good survival characteristics, whilst p21-/p53+ patients did poorly (p=0.008). The p21-/p53- patients overall did intermediately well, but Ki67-defined cellular proliferation analysis of these revealed two subclasses: those with high proliferation and poor survival times resembling the p21-/p53+ phenotype, and those with less proliferative tumours with good survival, similar to the p21+/p53- group. The significance of these results is discussed in the light of recent research concerning the role of p21 and p53 in breast cancer aetiology.

P21WAF1 expression and endocrine response in breast cancer

An immunocytochemical assay for the p53-regulated protein product of the WAF1/Cip1 gene, p21WAF1 (p21), was developed and applied to archival primary breast tumour material from 91 patients whose subsequent recurrent disease was treated with assessable courses of endocrine therapy. Nuclear localization of p21 protein was observed in 76 (82·4 per cent) cases. Status cut-offs were established and 29 (31·9 per cent) were deemed negative, 39 (42·9 per cent) weakly positive, and 23 (25·3 per cent) strongly positive. p21 status was inversely correlated with p53 protein (p = 0·047) but did not relate to oestrogen receptor (ER) status, response to endocrine therapy, or time to further disease progression (TTP). Highly p21-positive patients had a significantly improved overall survival time (p = 0·020). Co-assessment of p21 and p53 subgroups revealed p21 + /p53 − patients to have good survival characteristics, whilst p21 − /p53+ patients did poorly (p = 0·008). The p21 − /p53− patients overall did intermediately well, but Ki67-defined cellular proliferation analysis of these revealed two subclasses: those with high proliferation and poor survival times resembling the p21 − /p53+ phenotype, and those with less proliferative tumours with good survival, similar to the p21 + /p53− group. The significance of these results is discussed in the light of recent research concerning the role of p21 and p53 in breast cancer aetiology. Copyright © 1999 John Wiley & Sons, Ltd.

Prognostic and Predictive Value of p53Prognostic and Predictive Value of p53 Edited by KlijnJ.G.M.. Available from Publication: September 1997. Available from Elsevier Science BV, P.O. Box 211, 1000 AE Amsterdam, The Netherlands, or from Elsevier Science Inc., P.O. Box 945, Madison Square Station, New York, NY 10160-0757, USA. Price: Price: US$95.00. ISBN: ISBN 0-444-82832-X.

Book ReviewsPrognostic and Predictive Value of p53 Mohammed AkhtarMD, FCAP Mohammed Akhtar Head, Division of Anatomic Pathology, Department of Pathology and Laboratory, Medicine (MBC 10), King Faisal Specialist Hospital and Research Centre, P.O. Box 3354 Riyadh 11211, Saudi Arabia Search for more papers by this author Published Online::1 Sep 1998https://doi.org/10.5144/0256-4947.1998.482SectionsPDF ToolsAdd to favoritesDownload citationTrack citations ShareShare onFacebookTwitterLinked InRedditEmail AboutIntroductionThis is the first of a new series of books published under the auspices of the European School of Oncology. As the title indicates, the book deals with the most important gene involved in carcinogenesis, namely, p53. The book consists of 10 articles written by different experts in the field. The first paper, by Thierry Soussi of Institut Curie, Paris, France, entitled "The p53 tumor suppressor gene: From molecular biology to clinical investigation," tries to bring together the current knowledge regarding molecular pathology of p53 and its role in the pathogenesis and management of various human cancers.The next four chapters primarily deal with the role of p53 in breast cancer and discuss such subjects as the role of p53 in the management of breast cancer, the significance of p53 protein accumulation in human breast cancer, the impact of p53 status on breast tumor biology and response to therapy, and the relation of p53 expression to tumor differentiation and endocrine response in breast cancer. An interesting article by G. Gasparini and A.L Harris discusses the relationship between p53 and angiogenesis in neoplasia. Although at present, the relationship between the two is limited and controversial, this appears to be an exciting area for future research. The final paper, by Ingo B. Runnebaum, discusses the role of p53 genotypes and haplotypes in risk assessment in cancer patients and the prospects of retroviral p53 transduction for gene therapy of breast cancer. This is extremely interesting and stimulating work which deals with transduction of wild type p53 in MDAMB231 breast cancer cells.Since 1979, when the p53 gene was first described, thousands of papers have been written underlying the importance of this gene. In 1993, it was declared to be the gene of the year. Since then, a lot has been learned about the clinical implications of p53 as it relates to clinical management and therapy of patients with a variety of cancers, especially breast cancer.The book would definitely appeal to pathologists and oncologists interested in the diagnosis, prognosis and management of cancer, as well as researchers involved in the study of the genesis and progression of cancer. If the first book is any indication, subsequent books published by the European School of Oncology are bound to be equally exciting. Previous article Next article FiguresReferencesRelatedDetails Volume 18, Issue 5September 1998 Metrics History Published online1 September 1998 InformationCopyright © 1998, Annals of Saudi MedicinePDF download

Quantitative imaging of immunocytochemical (pap) estrogen receptor staining patterns in breast cancer sections

"Receptogram Analysis" has been developed as a pattern-oriented approach for predicting endocrine response in breast cancer based upon quantification of the estrogen receptor immunocytochemical assay (ERICA), using a Quantimet Imaging System. Response prediction was evaluated in 58 stage III and IV patients receiving endocrine therapy (primarily Tamoxifen). The Receptogram is a composite of the univariate distributions of nuclear receptor content, IOD(S), and concentration (MOD), and their bivariate contour plot; where (S) is the calculated nuclear radius in section. MOD distributions were classified into four types based upon peak modality and kurtosis (I-IV), and contour plots were classified into four subtypes (A-D) based upon contour slope. Patients failing therapy were ERICA--or their receptogram revealed co-existent ER+ and ER- tumor cells (type II), highly skewed MOD distributions lacking defined peaks (type IV), or contours with nearly horizontal slope (type C). Response was realized in 9/16 type I patients, with a single positive MOD peak, and in 9/15 type III patients, with discrete, multimodal MOD peaks. In contrast, 0/8 type II, 0/12 type IV, and 0/10 type C patients were responders. Receptogram analysis was superior to cytosol assay (DCC) as a response discriminant: positive predictive value, 53% vs. 33%; negative predictive value, 100% vs. 75%; sensitivity, 100% vs. 83%; specificity, 68% vs. 23%; and accuracy, 78% vs. 41%, respectively. Alternately, patients were assigned to potentially responsive or non-responsive groups based upon thresholded mean receptor parameters: field MOD, mean nuclear MOD (NMOD), and mean NMOD(PF) where PF is the ER+ nuclear fraction. While these parameters correlated with DCC (r = .72, 0.69, and 0.69), they were only marginally better in predictive value.