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Molecular profiles of progesterone receptor loss in human breast tumors.

ABSTRACT: Patient prognosis and response to endocrine therapy in breast cancer correlate with protein expression of both estrogen receptor (ER) and progesterone receptor (PR), with poorer outcome in patients with ER+/PR- compared to ER+/PR+ tumors.To better understand the underlying biology of ER+/PR- tumors, we examined RNA expression (n > 1000 tumors) and DNA copy number profiles from five previously published studies of human breast cancers with clinically assigned hormone receptor status (ER+/PR+, ER+/PR-, and ER-/PR-).We identified an expression "signature" of genes with either elevated or diminished RNA levels specifically in ER+/PR+ compared to ER-/PR- and ER+/PR- tumors. We similarly identified a gene signature specific to ER-/PR- tumors. ER+/PR- tumors, on the other hand, were a mixture of three different subtypes: tumors manifesting the ER+/PR+ signature, tumors manifesting the ER-/PR- signature, and tumors not associating with ER+/PR+ or ER-/PR- tumors (which we considered "true" ER+/PR-). In analyses of both tamoxifen-treated and untreated patients, ER+/PR- breast cancers defined by RNA profiling were associated with poor patient outcome, worse than those with pure ER+/PR+ patterns; these differences were not observed when using clinical assays to assign ER and PR status. ER+/PR- tumors also showed twice as many DNA copy number gains or losses compared to ER+/PR+ and ER-PR- tumors. Targets of transcriptional up-regulation by specific oncogenic pathways, including PI3 K/Akt/mTOR, were enriched in both ER+/PR- and ER-/PR- compared to ER+/PR+ tumors.ER+/PR- tumors as defined by RNA profiling represent a distinct subset of breast cancer with aggressive features and poor outcome, despite being clinically ER+. Multigene assays derived from our gene signatures could conceivably provide an improved clinical assay for inferring PR status for prognostic and therapeutic purposes.

SUBMITTER: Creighton CJ

PROVIDER: S-EPMC2635926 | biostudies-literature | 2009 Mar

REPOSITORIES: biostudies-literature

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Molecular profiles of progesterone receptor loss in human breast tumors.

Creighton Chad J CJ Kent Osborne C C van de Vijver Marc J MJ Foekens John A JA Klijn Jan G JG Horlings Hugo M HM Nuyten Dimitry D Wang Yixin Y Zhang Yi Y Chamness Gary C GC Hilsenbeck Susan G SG Lee Adrian V AV Schiff Rachel R

Breast cancer research and treatment 20080419 2

<h4>Background</h4>Patient prognosis and response to endocrine therapy in breast cancer correlate with protein expression of both estrogen receptor (ER) and progesterone receptor (PR), with poorer outcome in patients with ER+/PR- compared to ER+/PR+ tumors.<h4>Methods</h4>To better understand the underlying biology of ER+/PR- tumors, we examined RNA expression (n > 1000 tumors) and DNA copy number profiles from five previously published studies of human breast cancers with clinically assigned ho ...[more]

PMID: 18425577

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Project description:IntroductionOf the nearly 1.4 million new cases of breast cancer diagnosed each year, a large proportion is characterized as hormone receptor negative, lacking estrogen receptors (ER) and/or progesterone receptors (PR). Patients with receptor-negative tumors do not respond to current steroid hormone-based therapies and generally have significantly higher risk of recurrence and mortality compared with patients with tumors that are ER- and/or PR-positive. Previous in vitro studies had shown that the progesterone metabolites, 5α-dihydroprogesterone (5αP) and 3α-dihydroprogesterone (3αHP), respectively, exhibit procancer and anticancer effects on receptor-negative human breast cell lines. Here in vivo studies were conducted to investigate the ability of 5αP and 3αHP to control initiation, growth, and regression of ER/PR-negative human breast cell tumors.MethodsER/PR-negative human breast cells (MDA-MB-231) were implanted into mammary fat pads of immunosuppressed mice, and the effects of 5αP and 3αHP treatments on tumor initiation, growth, suppression/regression, and histopathology were assessed in five separate experiments. Specific radioimmunoassays and gas chromatography-mass spectrometry were used to measure 5αP, 3αHP, and progesterone in mouse serum and tumors.ResultsOnset and growth of ER/PR-negative human breast cell tumors were significantly stimulated by 5αP and inhibited by 3αHP. When both hormones were applied simultaneously, the stimulatory effects of 5αP were abrogated by the inhibitory effects of 3αHP and vice versa. Treatment with 3αHP subsequent to 5αP-induced tumor initiation resulted in suppression of further tumorigenesis and regression of existing tumors. The levels of 5αP in tumors, regardless of treatment, were about 10-fold higher than the levels of 3αHP, and the 5αP:3αHP ratios were about fivefold higher than in serum, indicating significant changes in endogenous synthesis of these hormones in tumorous breast tissues.ConclusionsThe studies showed that estrogen/progesterone-insensitive breast tumors are sensitive to, and controlled by, the progesterone metabolites 5αP and 3αHP. Tumorigenesis of ER/PR-negative breast cells is significantly enhanced by 5αP and suppressed by 3αHP, the outcome depending on the relative concentrations of these two hormones in the microenvironment in the breast regions. The findings show that the production of 5αP greatly exceeds that of 3αHP in ER/PR-negative tumors and that treatment with 3αHP can effectively block tumorigenesis and cause existing tumors to regress. The results provide the first hormonal theory to explain tumorigenesis of ER/PR-negative breast tissues and support the hypothesis that a high 3αHP-to-5αP concentration ratio in the microenvironment may foster normalcy in noncancerous breast regions. The findings suggest new diagnostics based on the relative levels of these hormones and new approaches to prevention and treatment of breast cancers based on regulating the levels and action mechanisms of anti- and pro-cancer progesterone metabolites.

Project description:BackgroundSocial isolation is associated with accelerated breast cancer progression and increased disease recurrence and mortality, but the underlying biological mechanisms remain poorly understood. In preclinical models, beta-adrenergic signaling from fight-or-flight stress responses can stimulate prometastatic processes in the tumor microenvironment including upregulation of M2 macrophages, epithelial-mesenchymal transition (EMT), and lymphovascular invasion. This study examines whether the same pathways are upregulated in breast tumors from socially isolated cancer patients.MethodsEMT and M1/M2 macrophage gene expression programs were analyzed by genome-wide transcriptional profiling, and lymphatic and vascular density were assessed by immunohistochemistry in primary tumors from 56 early-stage breast cancer patients who were part of the UCLA RISE study. Social isolation was quantified by the Social Provisions Scale, and disease characteristics were assessed by medical record review. General linear models were used to quantify differential gene expression across risk factor groups. Linear regression models were used to examine associations between social isolation and lymphovascular invasion.ResultsTumors from socially isolated patients showed upregulated expression of genes involved in EMT (average score difference = +0.080 log2 mRNA abundance ± 0.034 standard error) and M2 macrophage polarization (+0.033 ± 0.014) as well as increased density of lymphatic vessels (β= -.29) but no difference in blood vessel density. TELiS promoter-based bioinformatics analyses indicated activation of CREB family transcription factors that mediate the gene-regulatory effects of β-adrenergic signaling (log2 fold-difference in promoter binding site prevalence: mean ± standard error = +0.49 ± 0.19).ConclusionsPrimary breast tumors from socially isolated patients show multiple prometastatic molecular alterations, providing a plausible biological pathway through which poor social support may accelerate breast cancer progression and defining new targets for intervention.

Project description:Background: Hormonal therapy using progestins, acting through the progesterone receptor (PR), is a well-established method to treat uterine endometrial hyperplasia and carcinoma. Recent population studies indicate that progestin exposure significantly reduces the incidence of ovarian, pancreatic and lung cancers in addition to endometrial cancer in women. This unexpected differentiating function of progestin in organs outside of the reproductive system led us to hypothesize that progestins/PR are protective against cancer development and progression in many tumor types. Methods: The Cancer Genome Atlas, Oncomine and Prognostic Databases were searched to determine the relative expression of PR in tumors from multiple sites, and clinical outcomes linked to PR expression were determined. In addition, mRNA and protein expression were evaluated using real-time PCR and Western blotting. Chromatin immunoprecipitation (ChIP) assay was performed to understand the PR downregulation mechanisms in tumor cells and patient samples. Methylation-specific PCR was conducted to survey the PR methylation status. The Student’s t-test were performed to determine significance. Flow cytometry was used to quantify apoptotic cells. Results: Low PR expression levels were consistently linked to less favorable clinical outcomes in endometrial, pancreatic, ovarian and non-small cell lung cancers. Clinical specimens and cell lines from these cancers demonstrate low levels of PR, and we now report that the mechanism for loss of PR is mediated through epigenetic repression. However, PR silencing can be overcome with epigenetic modulators. Histone deacetylase inhibitor (LBH589) and hypomethylating agent (5-aza-decitabine) restored functional PR expression at both the mRNA and protein levels and promoted marked cell death through induction of apoptosis in the presence of progesterone. Conclusions: Our studies support the possibility that progestin therapy in combination with epigenetic modulators, a concept we term “molecularly enhanced progestin therapy”, is an approach worthy of study for malignancies originating from tissues outside of the reproductive tract.

Project description:Simple Summary Most breast cancers co-express estrogen receptor α (ERα) and progesterone receptor (PgR). These cancers are sensitive to endocrine therapy and, in general, have superior outcomes. However, a subset of tumors expresses ERα but loses expression of PgR in various mechanisms. The processes driving the loss of PgR may cause resistance to hormonal treatment and a more aggressive clinical course. The current review summarizes current knowledge on the biology of ERα-positive PgR(−)negative breast cancer and discusses the associations between molecular mechanisms and clinical characteristics. Abstract Estrogen receptor α (ERα) and progesterone receptor (PgR) are crucial prognostic and predictive biomarkers that are usually co-expressed in breast cancer (BC). However, 12–24% of BCs present ERα(+)/PgR(−) phenotype at immunohistochemical evaluation. In fact, BC may either show primary PgR(−) status (in chemonaïve tumor sample), lose PgR expression during neoadjuvant treatment, or acquire PgR(−) phenotype in local relapse or metastasis. The loss of PgR expression in ERα(+) breast cancer may signify resistance to endocrine therapy and poorer outcomes. On the other hand, ERα(+)/PgR(−) BCs may have a better response to neoadjuvant chemotherapy than double-positive tumors. Loss of PgR expression may be a result of pre-transcriptional alterations (copy number loss, mutation, epigenetic modifications), decreased transcription of the PGR gene (e.g., by microRNAs), and post-translational modifications (e.g., phosphorylation, sumoylation). Various processes involved in the down-regulation of PgR have distinct consequences on the biology of cancer cells. Occasionally, negative PgR status detected by immunohistochemical analysis is paradoxically associated with enhanced transcriptional activity of PgR that might be inhibited by antiprogestin treatment. Identification of the mechanism of PgR loss in each patient seems challenging, yet it may provide important information on the biology of the tumor and predict its responsiveness to the therapy.

Dataset Information

Molecular profiles of progesterone receptor loss in human breast tumors.

Publications

Molecular profiles of progesterone receptor loss in human breast tumors.

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