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Search for other papers by Leigh C Murphy in
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Despite over 15 years of research, the exact role, if any, played by estrogen receptor β (ERβ) in human breast cancer remains elusive. A large body of data both in vitro and in vivo supports its role as an antiproliferative, pro-apoptotic factor especially when co-expressed with ERα. However, there is a smaller body of data associating ERβ with growth and survival in breast cancer. In clinical studies and most often in cell culture studies, the pro-growth and pro-survival activity of ERβ occurs in ERα-negative breast cancer tissue and cells. This bi-faceted role of ERβ is discussed in this review.
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The role of oestrogen receptor (ER) β in human breast cancer remains unclear. However, it is now apparent that when considering ER β in human breast cancer it is important to recognise two ER β expressing groups, one in which ER β is co-expressed with ER α and the other where ERβ is expressed alone. Emerging data support different functions between ER β when it is expressed alone and when it is co-expressed with ER α. With regard to the latter group (ER α +/ER β +), there are now 9 out of 10 retrospective clinical outcome studies published, that support the hypothesis that increased expression of ER β is associated with increased likelihood of response to endocrine therapy. The data strongly support undertaking prospective studies to determine if the addition of ERβ to ER α is clinically beneficial and whether to include both ER β and ER α when establishing clinically relevant cut-offs for defining ER status.
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Estrogen receptor alpha (ERα) regulates and is regulated by kinases involved in several functions associated with the hallmarks of cancer. The following literature review strongly suggests that distinct kinomes exist for ERα-positive and -negative human breast cancers. Importantly, consistent with the known heterogeneity of ERα-positive cancers, different subgroups exist, which can be defined by different kinome signatures, which in turn are correlated with clinical outcome. Strong evidence supports the interplay of kinase networks, suggesting that targeting a single node may not be sufficient to inhibit the network. Therefore, identifying the important hubs/nodes associated with each clinically relevant kinome in ER+ tumors could offer the ability to implement the best therapy options at diagnosis, either endocrine therapy alone or together with other targeted therapies, for improved overall outcome.
Department of Biochemistry and Medical Genetics, Manitoba Institute of Cell Biology, Deeley Research Centre, Faculty of Medicine
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Department of Biochemistry and Medical Genetics, Manitoba Institute of Cell Biology, Deeley Research Centre, Faculty of Medicine
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Department of Biochemistry and Medical Genetics, Manitoba Institute of Cell Biology, Deeley Research Centre, Faculty of Medicine
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Multiple sites of phosphorylation on human estrogen receptor α (ERα) have been identified by a variety of methodologies. Now with the emerging availability of phospho-site-specific antibodies to ERα, the relevance of phosphorylation of ERα in human breast cancer in vivo is being explored. Multiple phosphorylated sites in ERα can be detected in multiple breast tumor biopsy samples, providing evidence of their relevance to human breast cancer in vivo. Published data suggest that the detection in primary breast tumors of phosphorylation at some sites in ERα is associated with a better clinical outcome while phosphorylation at other sites is associated with a poorer clinical outcome most often in patients who have been treated with tamoxifen. This suggests the hypothesis that phospho-profiling of ERα in human breast tumors to establish an ‘ERα phosphorylation code’, may be a more accurate marker of prognosis and/or response to endocrine therapy in human breast cancer.
Deeley Research Centre, Department of Biochemistry and Microbiology, Department of Biochemistry and Medical Genetics, Department of Pathology and Laboratory Medicine, BC Cancer Agency, 2410 Lee Avenue, 3rd Floor Research, Victoria, British Columbia, Canada V8R 6V5
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Search for other papers by Leigh C Murphy in
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Deeley Research Centre, Department of Biochemistry and Microbiology, Department of Biochemistry and Medical Genetics, Department of Pathology and Laboratory Medicine, BC Cancer Agency, 2410 Lee Avenue, 3rd Floor Research, Victoria, British Columbia, Canada V8R 6V5
Deeley Research Centre, Department of Biochemistry and Microbiology, Department of Biochemistry and Medical Genetics, Department of Pathology and Laboratory Medicine, BC Cancer Agency, 2410 Lee Avenue, 3rd Floor Research, Victoria, British Columbia, Canada V8R 6V5
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The most important clinical biomarker for breast cancer management is oestrogen receptor alpha (ERα). Tumours that express ER are candidates for endocrine therapy and are biologically less aggressive, while ER-negative tumours are largely treated with conventional chemotherapy and have a poor prognosis. Despite its significance, the mechanisms regulating ER expression are poorly understood. We hypothesised that the inflammatory cytokine oncostatin M (OSM) can downregulate ER expression in breast cancer. Recombinant OSM potently suppressed ER protein and mRNA expression in vitro in a dose- and time-dependent manner in two human ER+ breast cancer cell lines, MCF7 and T47D. This was dependent on the expression of OSM receptor beta (OSMRβ) and could be blocked by inhibition of the MEKK1/2 mitogen-activated protein kinases. ER loss was also necessary for maximal OSM-induced signal transduction and migratory activity. In vivo, high expression of OSM and OSMR mRNA (determined by RT-PCR) was associated with reduced ER (P<0.01) and progesterone receptor (P<0.05) protein levels in a cohort of 70 invasive breast cancers. High OSM and OSMR mRNA expression was also associated with low expression of ESR1 (ER, P<0.0001) and ER-regulated genes in a previously published breast cancer gene expression dataset (n=321 cases). In the latter cohort, high OSMR expression was associated with shorter recurrence-free and overall survival in univariate (P<0.0001) and multivariate (P=0.022) analyses. OSM signalling may be a novel factor causing suppression of ER and disease progression in breast cancer.
Department of Immunology, Manitoba Institute of Cell Biology, Department of Biochemistry and Medical Genetics, University of Manitoba, 471 Apotex Centre 750 McDermot Avenue, Winnipeg, Manitoba, Canada R3E 0T5
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Department of Immunology, Manitoba Institute of Cell Biology, Department of Biochemistry and Medical Genetics, University of Manitoba, 471 Apotex Centre 750 McDermot Avenue, Winnipeg, Manitoba, Canada R3E 0T5
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Department of Immunology, Manitoba Institute of Cell Biology, Department of Biochemistry and Medical Genetics, University of Manitoba, 471 Apotex Centre 750 McDermot Avenue, Winnipeg, Manitoba, Canada R3E 0T5
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Department of Immunology, Manitoba Institute of Cell Biology, Department of Biochemistry and Medical Genetics, University of Manitoba, 471 Apotex Centre 750 McDermot Avenue, Winnipeg, Manitoba, Canada R3E 0T5
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Department of Immunology, Manitoba Institute of Cell Biology, Department of Biochemistry and Medical Genetics, University of Manitoba, 471 Apotex Centre 750 McDermot Avenue, Winnipeg, Manitoba, Canada R3E 0T5
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Although the role of estrogen signaling in breast cancer development has been extensively studied, the mechanisms that regulate the indispensable role of estrogen in normal mammary gland development have not been well studied. Because of the unavailability of culture system to maintain estrogen-receptor-positive (ERα+) cells in vitro, the molecular mechanisms that regulate estrogen/ERα signaling in the normal human breast are unknown. In the present study, we examined the effects of estrogen signaling on ERα+ human luminal progenitors using a modified matrigel assay and found that estrogen signaling increased the expansion potential of these progenitors. Furthermore, we found that blocking ERα attenuated luminal progenitor expansion and decreased the luminal colony-forming potential of these progenitors. Additionally, blocking ERα decreased H19 expression in the luminal progenitors and led to the development of smaller luminal colonies. We further showed that knocking down the H19 gene in the luminal progenitors significantly decreased the colony-forming potential of the luminal progenitors, and this phenotype could not be rescued by the addition of estrogen. Lastly, we explored the clinical relevance of the estrogen–H19 signaling axis in breast tumors and found that ERα+ tumors exhibited a higher expression of H19 as compared with ERα− tumors and that H19 expression showed a positive correlation with ERα expression in those tumors. Taken together, the present results indicate that the estrogen–ERα–H19 signaling axis plays a role in regulating the proliferation and differentiation potentials of the normal luminal progenitors and that this signaling network may also be important in the development of ER+ breast cancer tumors.
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Deeley Research Centre, Translational Gastroenterology Unit, Department of Biochemistry and Medical Genetics and the Manitoba Institute of Cell Biology, Department of Biochemistry and Microbiology, Department of Pathology and Laboratory Medicine, British Columbia Cancer Agency, 2410 Lee Avenue, Victoria, British Columbia, Canada V8R 6V5
Deeley Research Centre, Translational Gastroenterology Unit, Department of Biochemistry and Medical Genetics and the Manitoba Institute of Cell Biology, Department of Biochemistry and Microbiology, Department of Pathology and Laboratory Medicine, British Columbia Cancer Agency, 2410 Lee Avenue, Victoria, British Columbia, Canada V8R 6V5
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It is becoming clear that inflammation-associated mechanisms can affect progression of breast cancer and modulate responses to treatment. Estrogen receptor alpha (ERα (ESR1)) is the principal biomarker and therapeutic target for endocrine therapies in breast cancer. Over 70% of patients are ESR1-positive at diagnosis and are candidates for endocrine therapy. However, ESR1-positive tumours can become resistant to endocrine therapy. Multiple mechanisms of endocrine resistance have been proposed, including suppression of ESR1. This review discusses the relationship between intratumoural inflammation and endocrine resistance with a particular focus on inflammation-mediated suppression of ESR1.
Department of Biochemistry and Medical Genetics, Manitoba Institute of Cell Biology, Department of Structural and Cellular Biology, Manitoba Breast Tumour Bank, Tumour Tissue Repository and Deeley Research Centre, Faculty of Medicine
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Department of Biochemistry and Medical Genetics, Manitoba Institute of Cell Biology, Department of Structural and Cellular Biology, Manitoba Breast Tumour Bank, Tumour Tissue Repository and Deeley Research Centre, Faculty of Medicine
Department of Biochemistry and Medical Genetics, Manitoba Institute of Cell Biology, Department of Structural and Cellular Biology, Manitoba Breast Tumour Bank, Tumour Tissue Repository and Deeley Research Centre, Faculty of Medicine
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Department of Biochemistry and Medical Genetics, Manitoba Institute of Cell Biology, Department of Structural and Cellular Biology, Manitoba Breast Tumour Bank, Tumour Tissue Repository and Deeley Research Centre, Faculty of Medicine
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To determine the relationship of the multiple sites of oestrogen receptor α (ERα) phosphorylation to clinical outcome after tamoxifen therapy, sections from tissue microarrays representing over 300 ER+ breast cancers from patients who were treated with surgery+radiation and then tamoxifen were used for immunohistochemical determination of total ERα, p-S104/106-ERα, p-S118-ERα, p-S167-ERα, p-S282-ERα, p-S294-ERα, p-T311-ERα and p-S559-ERα. Relationships of phosphorylated ERα to overall and relapse-free survival (RFS; breast cancer death or recurrence) were tested using single (univariate) and multiple (multivariate) predictor statistical models. Large tumour size, node positivity, high grade, progesterone receptor (PR) negative status and low levels of p-S282-ERα were significantly associated with reduced overall survival (OS). Along with tumour size and node status, a novel phosphorylation score (P7 score ≥3), taking into account all seven p-ERα sites, was significantly associated with reduced OS in univariate and multivariate analyses (hazard ratio (HR)=2.24, 95% confidence interval (CI) 1.15–4.34, n=335; P=0.018). Along with tumour size, node status, grade and PR status, a high P7 score (≥3) was significantly associated with reduced RFS in univariate and multivariate analyses (HR=1.71, 95% CI 1.03–2.86, n=332; P=0.039). Since ERα is the site at which integration of diverse signals occurs to regulate breast cancer growth and survival, the ERα phosphorylation score may be a surrogate marker of the balance between oestrogen-dependent and crosstalk-dependent receptor activity, and is potentially a prognostic marker of clinical outcome in a tamoxifen-treated population of patients.