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Resistance to endocrine therapy is a major clinical challenge in estrogen receptor (ER)-positive breast cancer. Obesity is associated with the clinical response to ER-positive breast cancers; however, the mechanism underlying obesity-induced resistance to endocrine therapy in ER-positive breast cancers remains unclear. In this study, we investigated the molecular mechanisms underlying obesity-induced resistance to tamoxifen (TAM), an anti-estrogen agent, in the ER-positive breast cancer cell line MCF-7 using differentiated adipocyte-conditioned medium (D-CM). Treatment of the cells with D-CM promoted TAM resistance by reducing TAM-induced apoptosis. The expression levels of the ERα target genes were higher in D-CM-treated cells than those in untreated ones. In contrast, when the cells were cultured in the presence of TAM, the expression levels were decreased, with or without D-CM. Moreover, the expression of the markers for cancer stem-like cells (CSCs) and mammosphere formation was enhanced by co-treating with D-CM and TAM, compared with TAM alone. The phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway was activated in MCF-7 cells by D-CM treatment, even in the presence of TAM. Inhibition of the PI3K/Akt/mTOR pathway decreased the expression levels of the CSC markers, suppressed mammosphere formation, and resensitized to TAM via inducing apoptosis in D-CM-treated cells. These results indicate that the conditioned medium of differentiated adipocytes promoted TAM resistance by inducing the CSC phenotype through activation of the PI3K/Akt/mTOR pathway in ER-positive breast cancer cells. Thus, the PI3K/Akt/mTOR pathway may be a therapeutic target in obese patients with ER-positive breast cancers. • D-CM promotes TAM resistance in ER-positive breast cancer cells. • TAM-induced cancer stem-like cell features are associated with acquisition of TAM resistance. • D-CM enhances TAM-induced stemness in ER-positive breast cancer cells. • PI3K/Akt/mTOR pathway is a potential target for obesity-induced TAM resistance. [ABSTRACT FROM AUTHOR]

Purpose: This study evaluated the proportion of premenopausal women who experience persistent ovarian escape (OE) while receiving ovarian suppression (OS) therapy for estrogen receptor‐positive (ER+) breast cancer treatment. The study also examined clinical factors that may predispose to higher risk of persistent OE. Materials and Methods: This was a retrospective, "real‐world" study to evaluate premenopausal women receiving adjuvant endocrine OS therapy. The primary objective was to measure the percentage of persistent OE within the first 3 months of OS injections (using either leuprolide or goserelin). The secondary objective was to associate baseline clinical data (age, body mass index [BMI], and previous chemotherapy) with the probability of OE. Results: Of the 46 patients included in this analysis, 11 (23.9%) women did not achieve OS within 3 months. Three women (6.5%) remained in OE at 12 months. Older age (odds ratio, 0.86; confidence interval, 0.76–0.98, p =.024) was associated with lower chance of developing OE. BMI, previous chemotherapy, and drug used (tamoxifen versus aromatase inhibitor) did not correlate with the likelihood of OE in this patient cohort. Conclusion: Among the premenopausal women who did not attain complete ovarian suppression, young age was a significant risk factor for likelihood of OE. Although the clinical relevance of this finding is not yet known, it should prompt further studies to determine whether inadequate OS is associated with higher recurrence risk for patients with ER+ breast cancer. Implications for Practice: Because up to a quarter of premenopausal women do not attain adequate ovarian suppression within the first 3 months of gonadotropin‐releasing hormone (GnRH) agonist therapy, bloodwork should be checked to ascertain hormone levels prior to starting aromatase inhibitor therapy, and at regular intervals, for these women. It is recommended that premenopausal women with ER+ breast cancer and a high risk of disease recurrence should receive ovarian suppression with adjuvant endocrine therapy; however, failure to achieve maximally suppressed estradiol levels could contribute to worse outcomes for ER+ breast cancer survivors. This article assesses premenopausal patients with ER+ breast cancer who did not achieve maximal estradiol suppression within 3 months of treatment and evaluates the contributing risk factors. [ABSTRACT FROM AUTHOR]

Breast cancer is the most frequent malignant tumor in women, and the estrogen receptor (ER) plays a vital role in the vast majority of breast cancers. The purpose of the present study was to identify the significant genes regulated by ER in ER-positive breast cancer and to explore their expression pattern changes when tamoxifen or fulvestrant resistance occurs. For this purpose, the gene expression profiles GSE11324, GSE27473, and GSE5840 from the Gene Expression Omnibus database were used, which contain gene expression data from MCF7 cells treated with estrogen, MCF7 cells with silencing of ER, and tamoxifen- and fulvestrant-resistant MCF7 cells treated with estrogen (17β-estradiol), respectively. Differentially expressed genes (DEGs) between the treatment group and negative control were identified and subjected to pathway enrichment and protein–protein interaction (PPI) analyses. There were 230 DEGs in common among the three datasets, including 160 genes positively regulated by ER and 70 genes negatively regulated by ER. DEGs mainly showed enrichment for pathways in cancer, progesterone-mediated oocyte maturation, RNA transport, glycerophospholipid metabolism, oocyte meiosis, platelet activation, and so on. PPI network and modular analysis selected three significant clusters containing 19 genes. A total of 44 genes were involved in Kyoto Encyclopedia of Gene and Genome pathway results or PPI modular analysis, and 16 of them were found to correlate with relapse-free survival in patients with ER+/human epidermal growth factor receptor 2-negative breast cancer who had undergone endocrine therapies only. Some of the genes' expression patterns were different among wild-type, tamoxifen-resistant, and fulvestrant-resistant MCF7 cells such as DDX18 , ANAPC7 , MAD2L1 , RSL1D1 , and CALCR , etc., indicating different resistance mechanisms and potential prognostic markers or therapeutic targets for fulvestrant- or tamoxifen-resistant breast cancer. [ABSTRACT FROM AUTHOR]

Aberrant ERα signaling and altered circadian rhythms are both features of ER-positive breast cancer, however, the molecular interaction between them is still not fully understood. Herein, we analyzed the interplay between the circadian rhythm molecule DEC1 and ERα and its effect on the proliferation of ER-positive breast cancer cells, providing a new clue for clarifying the pathogenesis of breast cancer. In this study, we revealed that DEC1 negatively regulates the proliferation of ER-positive breast cancer MCF-7 cells through interaction with ERα protein. DEC1 co-localized with ERα in the nucleus of MCF7 cells, stabilized ERα protein independently of its transcriptional activity and without affecting by estrogen stimulation and inhibited the degradation of ERα mediated by CHX in a time-dependent manner. Moreover, results from luciferase reporter assay showed that overexpression of DEC1 significantly inhibits ERα-mediated transcriptional activity in a dose-dependent manner. These results together suggested that DEC1 may serve as a co-repressor of ERα in ER-positive breast cancer. Although DEC1 improved the stability of ERα and alleviated protein degradation, DEC1 inhibited the proliferation of MCF7 cells by decreasing ERα-mediated signal transduction. • DEC1 negatively regulates the proliferation of ER-positive breast cancer MCF-7 cells. • Overexpression of DEC1 increases the stability of ERα protein. • DEC1 is an ERα-interacting protein. • Overexpression of DEC1 represses ERα-mediated transcriptional activation. [ABSTRACT FROM AUTHOR]

Despite the established benefits of long‐term endocrine therapy, women with hormone receptor‐positive breast cancer remain at risk for late relapse. The basis of this is multi‐factorial including genetic, epigenetic, and host factors. In this study we have explored the epigenetic regulation of estrogen receptor (ER)‐dependent molecular and cellular phenotype by hsa‐miR‐18a‐5p using well‐established human ER‐positive (ER+) breast cancer cell lines. miR‐18a was overexpressed in MCF7 and ZR‐75‐1 and this led to an increase in the proliferative ability of the cells and concurrently resulted in decreased expression of luminal markers and higher expression of the basal marker, cytokeratin 14. The cells became more migratory with a significant repression of E‐cadherin and activation of the Wnt noncanonical pathway. We observed an activation of the planar cell polarity (PCP) pathway with increased activation of JNK pathway and eventually change in actin dynamics. There was increased F‐actin polymerization in cells with higher expression of miR‐18a. Examination of miR‐18a expression in a set of human ER+ breast cancer specimens showed a negative correlation between miR‐18a and ESR1 transcripts as well as ER protein. Kaplan‐Meier survival analysis of the cohort stratified by tumor hsa‐miR‐18a‐5p levels produced significant differences in disease‐free survival (log rank P <.05). This observation was independently validated in the METABRIC cohort. These data provide support for a role of hsa‐miR‐18a‐5p in altering the proliferative and migratory behavior of ER+ cells and its potential utility as a prognostic marker in clinical ER+ breast cancers. [ABSTRACT FROM AUTHOR]

• SA could significantly enhance ER-positive breast cancer cell proliferation via inducing cell cycle progression. • NF-κB activation is required for SA-induced ER-positive breast cancer cell proliferation. • MiR-300-mediated IκBα down-regulation is responsible for SA induced NF-κB activation. Shikimic acid (SA), a widely-known hydroaromatic compound enriched in Bracken fern and Illicium verum (also known as Chinese star anise), increases the risk of gastric and esophageal carcinoma, nevertheless, the influence of SA on breast cancer remains indistinct. Herein we found that, with models in vitro, SA significantly promoted estrogen receptor(ER) positive cells proliferation and NF-κB activation was involved in it. Moreover, our data showed that IκBα, a critically endogenous inhibitor of NF-κB, was repressed. Subsequently, we found increase of miR-300 by SA treatment sand miR-300 could target IκBα mRNA. Additionally, inhibition of miR-300 abrogated the repression of IκBα by SA. As a result, miR-300 was also involved in NF-κB activation and breast cancer cells proliferation promotion due to SA exposure. Taken together, with ER-positive breast cancer cell models in vitro, MCF-7 and T47D, our results implied that SA promoted breast cancer cells proliferation via a miR-300-induced NF-κB dependent pathway controlling cell cycle proteins. [ABSTRACT FROM AUTHOR]

Oestrogen receptor (ER)-positive breast cancer is one of the common forms of breast cancer affecting women worldwide. ER-positive breast cancer patients are subjected to anti-oestrogen therapy such as selective oestrogen receptor modulator (SERM) and aromatase inhibitors (AIs). Recently, the emergence of resistance to anti-oestrogen treatment is under intensive focus. The different mechanisms postulated to explain the occurrence of resistance in ER-positive breast cancer treatment include the loss of ER function and the crosstalk between signalling pathways in cancer cells. Recent literature highlighted that the cholesterol biosynthesis pathway acts as a novel mechanism underlying resistance to oestrogen deprivation. The present study aimed to highlight the role of cholesterol biosynthesis in anti-oestrogen treatment resistance, putatively suggesting an alternative plant-based treatment using andrographolide from Andrographis paniculata. The hypolipidaemic effect of andrographolide can be utilised to prevent the resistance in the treatment of ER-positive breast cancer contributed by cholesterol biosynthesis. [ABSTRACT FROM AUTHOR]

Estrogen receptors (ERs) are involved in the development of many types of malignant tumors, in particular, breast cancer. Among others, ERs affect cell growth, proliferation, and differentiation. The microRNA (miRNA) miR‐142‐3p has been shown to inhibit carcinogenesis by regulating various cellular processes, including cell cycle progression, cell migration, apoptosis, and invasion. It does so via targeting molecules involved in a range of signaling pathways. We surgically collected 20 ER‐positive breast cancer samples, each with matched adjacent normal breast tissue, and measured the expression of miR‐142‐3p via quantitative real‐time polymerase chain reaction (qRT‐PCR). Bioinformatics methods, luciferase reporter assay, qRT‐PCR, and western blot analysis were used to assess whether miR‐142‐3p could target ESR1, which encodes the estrogen receptor, in ER‐positive breast cancer cells and patient samples. We also restored miRNA expression and performed cell viability, cytotoxicity, and colony formation assays. Western blot analysis and qRT‐PCR were used to study the expression of apoptosis and stemness markers. We found that miR‐142‐3p is downregulated in ER‐positive breast cancers. Restoration of miR‐142‐3p expression in ER‐positive breast cancer cells reduced cell viability, induced apoptosis via the intrinsic pathway and decreased both colony formation and the expression of stem cell markers. Bioinformatic analysis predicted miR‐142‐3p could bind to 3′‐untranslated region ESR1 messenger RNA (mRNA). Consistently, we demonstrated that miR‐142‐3p reduced luciferase activity in ER‐positive breast cancer cells, and decreased ESR1 expression in both mRNA and protein levels. The results revealed miR‐142‐3p and ESR1 expression correlated negatively in ER‐positive breast cancer samples. The results suggest miR‐142‐3p acts as a tumor suppressor via multiple mechanisms. Thus, restoration of miR‐142‐3p expression, for example, via miRNA replacement therapy, may represent an effective strategy for the treatment of ER‐positive breast cancer patients. [ABSTRACT FROM AUTHOR]

Abstract Estrogen receptor (ER) antagonist, tamoxifen has been universally used for the treatment of the ER-positive breast cancer; however, the inevitable emergence of resistance to tamoxifen obstructs the successful treatment of this cancer. So, there is an immediate requirement for the search of a novel therapeutic target for treatment of this cancer. Acquired tamoxifen-resistant breast cancer cell lines MCF-7 (MCF-7/TAM-R) and T47D (T47D/TAM-R) showed higher apoptotic resistance accompanied by induction of pro-survival autophagy compared to their parental cells. Besides, tamoxifen resistance was associated with reduced production of ATP and with overexpression of glycolytic pathways, leading to induced autophagy to meet the energy demand. Further, our study revealed that LDHA; one of the key molecules of glycolysis in association with Beclin-1 induced pro-survival autophagy in tamoxifen-resistant breast cancer. Mechanistically, pharmacological and genetic inhibition of LDHA reduced the pro-survival autophagy, with the restoration of apoptosis and reverting back the EMT like phenomena noticed in tamoxifen-resistant breast cancer. In total, targeting LDHA opened a novel strategy to interrupt autophagy and tamoxifen resistance in breast cancer. Highlights • LDHA regulates tamoxifen resistance in breast cancer. • Protective autophagy is induced in tamoxifen resistant breast cancer. • Glycolysis controls autophagy in tamoxifen resistant breast cancer. • LDHA modulates autophagy in tamoxifen resistant breast cancer. • LDHA encourages EMT in tamoxifen resistant breast cancer. [ABSTRACT FROM AUTHOR]

Connexins are widely supported as tumor suppressors due to their downregulation in cancers, nevertheless, more recent evidence suggests roles for connexins in facilitating tumor progression in later stages, including metastasis. One of the key factors regulating the expression, modification, stability, and localization of connexins is hormone receptors in hormone-dependent cancers. It is reasonable to consider that hormones/hormone receptors may modulate connexins expression and play critical roles in the cellular control of connexins during breast cancer progression. In estrogen receptor (ER)-positive breast cancers, tamoxifen and fulvestrant are widely used therapeutic agents and are considered to alter ER signaling. In this present study, we investigated the effects of fulvestrant and tamoxifen in Cx43 expression, and we also explored the role of Cx43 in ER-positive breast cancer migration and the relationship between Cx43 and ER. The involvement of estrogen/ER in Cx43 modulation was further verified by administering tyrosine kinase inhibitors and chemotherapeutic agents. We found that inhibition of ER promoted the binding of E3 ligase Nedd4 to Cx43, leading to Cx43 ubiquitination. Furthermore, inhibition of ER by fulvestrant and tamoxifen phosphorylated p38 MAPK, and inhibition of Rac, MKK3/6, and p38 reversed fulvestrant-reduced Cx43 expression. These findings suggest that Cx43 expression which may positively regulate cell migration is ER-dependent in ER-positive breast cancer cells. [ABSTRACT FROM AUTHOR]

Tamoxifen (Tam) has been the first-line therapy for estrogen receptor-positive breast cancer since its FDA-approval in 1998. Tam-resistance, however, presents a challenge and the mechanisms that drive it have yet to be fully elucidated. The non-receptor tyrosine kinase BRK/PTK6 is a promising candidate as previous research has shown that BRK knockdown resensitizes Tam-resistant breast cancer cells to the drug. However, the specific mechanisms that drive its importance to resistance remain to be investigated. Here, we investigate the role and mechanism of action of BRK in Tam-resistant (TamR), ER+, and T47D breast cancer cells using phosphopeptide enrichment and high throughput phopshoproteomics analysis. We conducted BRK-specific shRNA knockdown in TamR T47D cells and compared phosphopeptides identified in these cells with their Tam-resistant counterpart and parental, Tam-sensitive cells (Par). A total of 6492 STY phosphosites were identified. Of these sites, 3739 high-confidence pST sites and 118 high-confidence pY sites were analyzed for significant changes in phosphorylation levels to identify pathways that were differentially regulated in TamR versus Par and to investigate changes in these pathways when BRK is knocked down in TamR. We observed and validated increased CDK1 phosphorylation at Y15 in TamR cells compared to BRK-depleted TamR cells. Our data suggest that BRK is a potential Y15-directed CDK1 regulatory kinase in Tam-resistant breast cancer. [ABSTRACT FROM AUTHOR]

Estrogen receptors (ERs) play a major role in the growth of human breast cancer cells. A selective estrogen receptor down-regulator (SERD) that acts as not only an inhibitor of ligand binding, but also induces the down-regulation of ER, would be useful for the treatment for ER-positive breast cancer. We previously reported that tamoxifen derivatives, which have a long alkyl chain, had the ability to down-regulate ERα. With the aim of expanding range of the currently available SERDs, we designed and synthesized raloxifene derivatives, which had various lengths of the long alkyl chains, and evaluated their SERD activities. All compounds were able to bind ERα, and RC10, which has a decyl group on the amine moiety of raloxifene, was shown to be the most potent compound. Our findings suggest that the ligand core was replaceable, and that the alkyl length was important for controlling SERD activity. Moreover, RC10 showed antagonistic activity and its potency was superior to that of 4,4′-(heptane-4,4-diyl)bis(2-methylphenol) ( 18 ), a competitive antagonist of ER without SERD activity. These results provide information that will be useful for the development of promising SERDs candidates. [ABSTRACT FROM AUTHOR]

Anterior gradient protein (AGR) 3 is a highly related homologue of pro-oncogenic AGR2 and belongs to the family of protein disulfide isomerases. Although AGR3 was found in breast, ovary, prostate, and liver cancer, it remains of yet poorly defined function in tumorigenesis. This study aimed to determine AGR3 expression in a cohort of 129 primary breast carcinomas and evaluate the clinical and prognostic significance of AGR3 in these tumors. The immunohistochemical analysis revealed the presence of AGR3 staining to varying degrees in 80% of analyzed specimens. The percentage of AGR3-positive cells significantly correlated with estrogen receptor, progesterone receptor (both P<0.0001) as well as low histological grade (P=0.003), and inversely correlated with the level of Ki-67 expression (P<0.0001). In the whole cohort, AGR3 expression was associated with longer progressionfree survival (PFS), whereas AGR3-positive subgroup of low-histological grade tumors showed both significantly longer PFS and overall survival. In conclusion, AGR3 is associated with the level of differentiation, slowly proliferating tumors, and more favorable prognosis of breast cancer patients. [ABSTRACT FROM AUTHOR]

Aims Triple-negative breast cancer ( TNBC) is responsible for a disproportionate number of breast cancer ( BC) deaths, owing to its intrinsic aggressiveness and a lack of treatment options, especially targeted therapies. Thus, there is an urgent need for the development of better targeted treatments for TNBC. Molecular alteration of AKT-3 was previously reported in oestrogen receptor ( ER)-positive BC. AKT-3 has also been suggested to play a role in hormone-unresponsive BC. The aim of this study was to investigate molecular alterations of AKT-3 in TNBC, to perform associated survival analysis, and to compare these findings with the incidence of AKT-3 molecular alterations in ER-positive BC. Results Our study revealed AKT-3 amplification and deletions in 11% (9/82) and 13% (11/82) of TNBCs, respectively. In contrast, 1% (2/209) of ER-positive BCs were found to have AKT-3 amplifications and deletions. A higher prevalence of AKT-3 copy number gains was observed in TNBC [26% (21/82)] than in ER-positive BC [9% (19/209)]. AKT-3 amplification together with Akt-3 protein expression was negatively associated with recurrence-free survival in TNBC. Furthermore, a negative association between high AKT-3 copy number and recurrence-free survival was observed. Conclusion AKT-3 amplification could represent a potentially relevant oncogenic event in a subset of TNBCs that may, in turn, select cells sensitive to Akt-3 inhibitors. [ABSTRACT FROM AUTHOR]

Breast cancer stem cells (BCSC) play critical roles in the acquisition of resistance to endocrine therapy in estrogen receptor (ER)-positive (ER + ve) breast cancer (BC). The resistance results from complex alterations involving ER, growth factor receptors, NOTCH, Wnt/β-catenin, hedgehog, YAP/TAZ, and the tumor microenvironment. These mechanisms are likely converged on regulating BCSCs, which then drive the development of endocrine therapy resistance. In this regard, hormone therapies enrich BCSCs in ER + ve BCs under both pre-clinical and clinical settings along with upregulation of the core components of "stemness" transcriptional factors including SOX2, NANOG, and OCT4. SOX2 initiates a set of reactions involving SOX9, Wnt, FXY3D, and Src tyrosine kinase; these reactions stimulate BCSCs and contribute to endocrine resistance. The central contributions of BCSCs to endocrine resistance regulated by complex mechanisms offer a unified strategy to counter the resistance. ER + ve BCs constitute approximately 75% of BCs to which hormone therapy is the major therapeutic approach. Likewise, resistance to endocrine therapy remains the major challenge in the management of patients with ER + ve BC. In this review we will discuss evidence supporting a central role of BCSCs in developing endocrine resistance and outline the strategy of targeting BCSCs to reduce hormone therapy resistance. [ABSTRACT FROM AUTHOR]