Hormone Resistance and Hypersensitivity (Endocrine Development)

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The absence of overt clinical or biochemical pathology in the parents of the affected sisters could be due to an adequately compensated heterozygotic defect. The New World primate physiological and biochemical syndrome and the two pathological human multiple steroid resistance syndrome cases described by New et al. The likelihood that a coregulator is affected in multiple steroid resistance is high, and the search for altered coregulators should continue in the nonhuman primates and the patients.

On the other hand, the presence of amplification of SRC-3 in certain human breast and ovarian cancers suggests that this coactivator might be responsible for excessive tumor growth, through hypersensitization of the estrogen receptor signal transduction pathway In this instance, a clonal somatic mutation of the coactivator or of one of its regulatory molecules may have led to breast or ovarian tumorigenesis, even though the systemic secretion of estrogen may have been entirely normal in the affected patients.

Another imputed human glucocorticoid hypersensitivity state due to steroid coactivator hyperfunction is systemic infection with HIV-1, characterized by profound immunosuppression with a shift of the T cell helper h phenotype from Th1 to Th2, as well as by myopathy and muscle atrophy, both known effects of glucocorticoid excess It has been suggested that Vpr, an accessory HIV-1 protein, may be in part responsible for these manifestations by interacting with glucocorticoid receptors, host coactivators and TAF, and by exerting marked glucocorticoid coactivator activity in the immune system and muscle Table 2.


Thyroid hormone resistance - Wikipedia

Now that physicians have been alerted to the pathogenic potential of altered coregulators, it is quite likely that more steroid hormone-related syndromes with diverse, albeit logically explained, clinical pictures will be discovered. Some of these syndromes will be admittedly rare, but others may be subtle and common.

A good place to start searching for alterations of steroid receptor coregulator molecules is in already recognized syndromes of steroid hormone resistance or hypersensitivity, in which the pathogenicity of the steroid receptor and other known noncoregulator postreceptor steps have been excluded. Importantly, however, the coregulators of steroid hormones should be examined as potential participants in the pathogenesis of common polygenic disorders, such as obesity and the insulin-resistance visceral fat syndrome, the polycystic ovary syndrome, hypertension, major depression, autoimmune disorders, infertility, and so on, in which the glucocorticoid, mineralocorticoid and sex steroid signal transduction systems may be pathophysiologically involved 25 , The autonomous strong AF1 pertains to the type 1 or classical receptor subclass comprised by the receptors for glucocorticoids, mineralocorticoids, androgens, estrogens, and progesterone.

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Putative corepressor left and coactivator right transcription initiation complexes for nuclear receptors. The former are associated with transcriptionally inaccessible chromatin via deacetylation of histone tails and condensation of the DNA strands around the nucleosomes; the latter are associated with transcriptionally accessible chromatin via acetylation of histone tails and decondensation of DNA.

The latter complex is succeeded by further accumulation of protein complexes essential for further interaction with and activation of the polymerase II machinery. Defective coactivator or excessive corepressor activity could lead to nuclear hormone resistance affecting multiple nuclear hormonal receptor systems. Protein X, unknown corepressor complex cofactors; protein Y, unknown coactivator complex cofactor s. Oxford University Press is a department of the University of Oxford.

It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide. Sign In or Create an Account. Sign In. Advanced Search. Article Navigation. Close mobile search navigation Article Navigation. Volume Article Contents. Oxford Academic. Google Scholar. Article history. Symptoms of the following disorders can be similar to those of GHI.

Comparisons may be useful for a differential diagnosis:.

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In addition to the genetic forms of GHI, failure to have a normal growth response despite adequate GH production is characteristic of a number of conditions including chronic illness, undernutrition, kidney disease, liver disease, and congenital syndromes. These conditions are often referred to as secondary GHI. Coffin-Siris syndrome is a disorder of unknown cause. It is present at birth and affects both sexes. It is chiefly characterized by feeding problems, frequent respiratory infections, and growth deficiencies. Cockayne syndrome is a progressive disorder which manifests itself during the second year of life.

It is characterized by a hypersensitivity to sunlight and growth retardation. Growth hormone deficiency GHD , in its most severe form, is very similar to primary GHI, the main difference being that in children with GHI, a high level of GH is present in the blood and the administration of recombinant GH does not result in normalization of growth. The cause of GHD is often unknown, but genetic defects have been described in the receptor for GH releasing hormone from the brain and in the GH molecule, as well as in factors that lead to other hormone deficiencies along with GH.

It can be treated fairly easily and reliably with injections of recombinant human GH. However, rapid head growth is not occurring as it is in hydrocephalus. There are many disorders that can cause short stature. A diagnosis of GHI is usually made when failure to grow is accompanied by the typical facial appearance and central chubbiness that suggests GH deficiency, but with the finding of elevated GH levels. For more information contact:. Treatment of GHI with recombinant human GH is not effective because the body cannot utilize the hormone to grow.

Recombinant IGF-I therapy is associated with a risk of hypoglycemia which can be prevented by feeding. Fortunately, long-term effects of hypoglycemia have not been seen. Information on current clinical trials is posted on the Internet at www. All studies receiving U.

For information about clinical trials sponsored by private sources, contact: www. Arlan L. Growth hormone insensitivity syndrome. In: Radovick S, ed. Principles and Practice of Pediatric Endocrinology. In: Lifshitz F, ed. Pediatric Endocrinology. Obesity, diabetes, and cancer: insight into the relationship from a cohort with growth hormone receptor deficiency. Absent GH counterregulation due to GH receptor deficiency with obesity and enhanced insulin sensitivity.

J Clin Endocrinol Metab. This review discusses in detail the various intricate and sophisticated web of pathways involved in ER signaling and highlights schemes for treatment. Figure 1. Mechanisms involved in endocrine resistance: Several proteins, soluble mediators and transcription factors are assimilated and function cohesively in a complex network, with each entity playing a unique role through the regulation of its own cascade of events as mentioned in each section of this review.

In the opinion of the authors, the immune system and the stem cells are at the center of dysregulation observed in the proteins and pathways involved. The soluble mediators, like hormones, cytokines, and chemokines all play a crucial role in BC cells becoming endocrine resistant. ER is a nuclear receptor and belongs to the steroid-thyroid-retinoid receptor superfamily 6. Both receptor subtypes share similarity at the protein level and are comprised of domains denoted as A to F Figure 2 27 , This region modulates the functions of the AF1 and AF2 domains Figure 2.

The DBD and dimerization site is present within the C domain. The nuclear localization signal is contained in the D domain. ER signaling can be triggered by nuclear and non-nuclear mechanisms. Both the AF1 and AF2 domains are crucial, but the AF2 activation serves as the binding region for coactivators and corepressors 48 , In this study, enhanced expression of Oct4 led to a tamoxifen dependent increase in the proliferative potential of the tumor.

This is important in the context of endocrine resistance, since the array of molecules mobilized by the ER is dependent on the organization of the E2 mediated ER-ERE complex In response to E2, activation of AF1 leads to a concomitant action on the AF2 assisted by a complex of transcription factors to bring about a concerted effect on the ER mediated transcription 60 , These studies go on to highlight how redundancy can play a crucial role between signaling pathways and lead to an activation of the ER followed by subsequent activation, transcription and translation of ER regulated genes under conditions with inadequate E2 This mechanism might lead to resistance against various endocrine therapies.

Figure 3. A Post-translational modifications of the ER. B Regulation by E2 at the molecular level: A schematic representation of the pathways and the associated small molecule inhibitors involved in endocrine resistance. In the non-classical nuclear mechanism of ER signaling, the functions are mediated by activation of membrane bound ER, that occurs within minutes by activating protein kinase cascades. This rapid non-nuclear mechanism is also referred to as membrane-initiated steroid signaling MISS pathway The responses are mediated via ER associated with caveolar rafts, which collaborate as dimers precisely with signaling adaptor proteins 64 , Recent evidence suggests an association of GPER expression with resistance to endocrine therapy 70 — Thus, the interactions between classical ER and GPER is important to reveal the complex crosstalk and activation of non-nuclear mechanisms of E2 76 , The various pathways are an interplay of events and act in tandem.

Thus, inhibition of one pathway or mode of E2 signaling does not completely abolish oestrogenic or ER regulatory actions. There is crosstalk between both nuclear and non-nuclear pathways and these effects are coactive and interdependent. Downregulation of ER is hypothesized as a cause of acquired resistance to tamoxifen, although it is not downregulated in approximately a quarter of tumors with acquired resistance to tamoxifen and a fifth of the tamoxifen resistant cancers will go on to be responsive to treatment with an AI or a SERM e.

Thus, it is the expression of ER, which determines response to endocrine therapy, and a lack of the ER is the principal cause of de novo resistance to endocrine therapy. Another theory suggests that an increase in the deacetylation of histones, which limits transcription by condensing the nucleosome structure, could be a cause of non-existent ER transcription Recently, reports suggest that despite dysregulated signaling through the ER by SERMs and inadequate expression of the receptor, the target genes affected promote specific phenotypic changes in BC subtypes Unsurprisingly, epigenetic mechanisms in the form of histone deacetylase inhibitors or demethylation agents are now being used in anti-cancer therapy 89 — In one recent Phase II study done by Munster et al.

Here, they were given either exemestane, an AI, with or without entinostat a benzamide HDACi and the combination arm again showed a benefit in terms of the progression-free survival PFS and overall survival when compared with the patients on exemestane alone Thus, HDACi's appear to be have an important role in reversing endocrine resistance. Mutations of the ER gene play a crucial role in the effectiveness of anti BC drugs. Although such mutations have not been detected in primary breast tumors, Fuqua et al. A recent study has indicated that constitutive transcriptional activity of the DG mutation in ER , leads to overexpression which in turn leads to enhanced proliferation, thereby conferring resistance to tamoxifen Another point mutation in ER nucleotide AG , leads to an enhanced response upon activation by E2 and has been associated with invasive BCs Such loss of regulation could contribute to the development of endocrine resistance as has been reported by Ellis et al.

In the last few years several studies have been done to provide a complete set of mutations that could cause BC although in primary tumors, no mutation has been identified in the ER 97 , 98 , In the metastatic scenario, several ER mutations have been identified by at least three other studies 97 — Essentially, a range of SERDs are being developed with differential activities as ER antagonists to combat the clinical effectiveness of fulvestrant due to poor bioavailability.

Evaluating and studying a variety of potent ER antagonists will promote the development of clinically effective SERDs In BC, the Progesterone Receptor PR also plays an important role and its signaling has been at the center of various targeted therapies, including the selective progesterone receptor modulators SPRM The PR is regulated by the ER and is required for mammary gland development.

Indeed, a study of PR mediated regulation of oncogenic genes in PR regulated BC models has yielded information on its varied actions Although normal mammary epithelial cells express separate receptors ER and PR on designated cells, the receptors are co-expressed in oncogenic cells A dominant pathway takes over the functions of another during targeted therapy, in one such instance, a loss of the PR during endocrine therapy leads to the cancer becoming more aggressive.

These patients have a poor survival outcome In another study by Mohammed et al. Receptor Tyrosine Kinases RTK are a family of receptors that are activated upon binding their respective ligands, which are mainly the growth factors, hormones or cytokines. An upregulation of RTKs is observed in breast cancer and is indicative of poor prognosis , A multitude of evidence suggests that inhibitors of RTK's can reverse therapeutic resistance in metastatic breast cancers Figure 3B. These studies show that ER works in concert with the ErbB family of proteins to foster and assist cancer cell proliferation.

Several retrospective clinical studies have shown the significance of growth factor signaling in both de novo as well as assumed endocrine resistance. While it was previously hypothesized that a loss in the expression of ER could lead to tamoxifen resistance, evidence suggests that only three quarter of tumors express the ER Upregulation of growth factor signaling in MCF7 cells, as well as HER2 in patients treated with tamoxifen, suggests a redundancy in the operation and thus the use of combination therapy may be beneficial Data from studies imply that tumors switch from HER2 to ER and vice versa as the preferred signaling pathway, with therapy toward HER2 leading to an activation of the ER pathway and vice-versa 82 , The dependence of the two pathways on each other is highlighted in MBC patients who have been treated with an AI or the ER downregulated with fulvestrant and have progressed with trastuzumab or lapatinib.

Here, patients treated with trastuzumab plus anastrozole, an AI, showed a benefit in terms of the PFS when compared with the women on anastrozole alone Recently, a study targeted the extracellular domain of HER2, which is responsible for HER2 homo- and heterodimerization. Signal transduction inhibitors are crucial mediators in overcoming endocrine resistant BC. The findings above are supported by clinical studies where tumors over expressing HER2 and AIB1 had a worse outcome with tamoxifen In a recent study done on AI treated patients, it was evidenced that AIB1 played an important role in regulating selective ER transcriptional activity and promoting tumor recurrence Clinical studies are being done using EGFR inhibitors in isolation or a combination therapy in order to address endocrine resistance.

Tumors driven by a HER2 amplified mechanism are known to be resistant to endocrine therapy , , Genetic polymorphisms in genes encoding IGF-I have been reported, and may contribute to an increased risk for BC , A study by Creighton et al. The profiled tumors exhibiting the IGF-I signature correlated with poor prognosis and was indicative of a poor outcome. Activating mutations of the FGFR gene have been shown to have oncogenic potential and driving resistance to endocrine therapy , The role of BGJ was evaluated and initial reports suggest a promising role in breast cancer progression and metastasis to the lung The study was terminated due to low numbers of enrolled patients, although the combination arm of treatment showed promising clinical activity in the FGF pathway-amplified subgroup.

In line with these findings, a phase Ib trial ClinicalTrials. According to another GWAS study, the four genomic locations associated with BC were rs, rs, rs, and rs, all of which were located on intron 2 of the FGFR2 gene Genetic fusions of the FGFR gene also represent a small proportion of aberrations and a causative agent in BC , , These studies suggest a prominent role for FGFR1 amplifications and that all future studies and trials could focus their therapeutic strategy at targeting and inhibiting FGFR1.

SYK is primarily expressed by a variety of hematopoietic cells ranging from B cells, mast cells, neutrophils to macrophages and functions in proliferation, differentiation and adhesion , Here, activation of the specific receptor B cell receptor promotes phosphorylation of immune-receptor tyrosine-based activation motifs ITAMs and recruitment, autophosphorylation of SYK SYK functions as a tumor suppressor in BC with a reduction in SYK expression being associated with poor prognosis and metastasis , In samples from patients, SYK expression is lost as the tumor progresses from ductal carcinoma in situ DCIS to invasive breast cancer , However, in various other solid cancers it has tumor promoting activity depending on the association of the cancer with inflammation BC sensitivity to endocrine treatment is impacted by the activity of both positive and negative cell cycle regulators Studies have shown that overexpression of positive cell cycle regulators like c-MYC, cyclins E1 and D , contribute to the development of endocrine resistance by activating CDKs , A separate study surmised a central role for E2F proteins, in that unliganded ER plays a role in the E2 deprived growth of long term E2 deprived BC cells by regulating a transcriptional machinery The CDKs are crucial cyclin dependent drivers in cell cycle, cell division and thus cancer.

In another study, luminal B-type BCs resistant to endocrine therapy were identified by a unique gene signature indicating a loss of RB protein The BC cell lines exhibiting non-luminal or the basal subtypes, presented with resistance to palbociclib The results from this trial presented with an extension in the PFS for the cohort of patients treated with ribociclib plus letrozole when compared with the placebo group of letrozole alone The triplet inhibitor trial ClinicalTrials.

Another study is recruiting to study the response of fulvestrant and pembrolizumab as a combination therapy ClinicalTrials. Li et al. PTEN may be downregulated through several mechanisms, including mutations, loss of heterozygosity, methylation, aberrant expression of regulatory microRNA, protein instability and activated mTOR signaling is also associated with Cowden's syndrome PTEN mutations PI3K is comprised of several isoforms of the regulatory p85 and a catalytic subunit p The above studies have also shown the importance of a crosstalk between the PI3K and ER pathway in antioestrogen resistance and suggested that combining a PI3K inhibitor with an ER down regulator is more effectual than either of them alone In contrast, inhibition of the pathways leads to sensitization in response to antioestrogens and other oncogenic pathways are activated upon E2 deprivation or inhibition of ER in the endocrine resistant scenario Two other interdependent factors, mTORC1 and mTORC2 are part of a positive feedback mechanism belonging to the PI3K pathway, which have independent regulatory mechanisms and exert their effects through distinct targets and mechanisms Upon inhibition of mTORC1, the alternate complex mTORC2 leads to an activation of the PI3K pathway, which indicated that inhibition of one arm of the pathway via inhibitor , led to activation of another arm and may not be sufficient to produce a clinical benefit Several trials have been done where inhibitors of PI3K pathway have been combined with endocrine therapy.

In a neoadjuvant study by Baselga et al. The combination of everolimus and exemestane was found to have a median PFS that was significantly much superior to the exemestane only arm When considering the benefit based on mutation site, it was more pronounced in the DG group due to a larger number of patients. Here too, patients in the combination arm showed an improved clinical benefit rate, time to progression, as well as an overall survival compared to patients treated with tamoxifen alone. This study stratified the patients based on primary and secondary endocrine therapy resistance and interestingly, patients with relapse after 6 months of AI treatment presented with an improvement in the PFS when compared to those patients that relapsed during adjuvant AI before 6 months on the treatment The two PARP inhibitors approved by the FDA are olaparib and talazoparib, with talazoparib having a higher potency than olaparib due to a mechanism of action called DNA trapping , McGlynn et al.

NF1 was one among the compendium of genes whose silencing led to tamoxifen resistance in MCF7 cells Elevated levels of c-SRC may be due to overexpression of growth factors , Upon treatment with tamoxifen, c-SRC activity is increased and this subsequently amplifies the extent of invasion and motility in BC cells Moreover, since c-SRC is essential in modulating tamoxifen resistance, and blocking its activity reverses tamoxifen resistance It is well-understood that the STAT proteins mediate cell proliferation and survival by regulating and influencing the activities of several other transcription factors and associated pathways.

Thyroid hormone resistance

It has been shown that the STAT3 and STAT5 signaling pathways are integrally involved in endocrine resistance and more so in the growth factor-stimulated cases. Yamashita et al. It not only creates a microenvironment suitable for stem cell survival, but also its invasiveness and metastatic capability. Gionet et al. Lemur tyrosine kinase 3 LMTK3 is a serine-threonine-tyrosine protein kinase involved in various cancers. Aberrant expression of the gene and polymorphisms within the gene serve as suitable biomarkers in cancer progression , In an elaborate experimental setup, a role for LMTK3 in endocrine resistance was confirmed Future studies could focus on its use as a valuable biomarker and therapeutic target.

The intra-tumoral pressure of oxygen O 2 serves as an important indicator of the possibility of tumor metastasis In BC, hypoxia is induced due to reduced oxygen levels becoming available at the site of the tumor due to their distance from functionally viable blood vessels, and it in this simmering tumor conducive and expansive microenvironment that activation of its main effector, hypoxia-inducible factors HIF takes place. They encompass the ability to regenerate or self-renew and initiate cancer progression, proliferation, migration and metastasis.

The stemness of these cells are correlated with poor prognosis and endocrine resistance. Interestingly the same study also highlighted the upregulation of SOX9 in tamoxifen resistant clinical samples. Xue et al. There are possibly many transcription factors and associated pathways that may transform a normal stem cell to a cancerous stem cell, although two of the well-defined ones are: NOTCH and Hedgehog Hh. The NF-kB pathway has been described elsewhere. The intracellular domain then translocates to the nucleus where it binds with co-activators to regulate transcription of target genes and thereby plays an important role in endocrine resistance NOTCH signaling has been shown to play a critical role in normal human mammary development and also regulation of cancer stem cells in both invasive carcinoma of the breast as well as ductal carcinoma in situ , Recently, it has been reported that Nicastrin, an essential subunit of gamma secretase, and NOTCH4 are key molecules involved in resistance to endocrine therapy and that the gamma secretase inhibitor GSI PF and anti-Nicastrin MAbs can possibly reverse and potentially re-sensitize endocrine resistant BCs WNT signaling has been reported to play an important role in BC stem cells With STAT3 and STAT5 being constitutively activated in cancers, they have also been shown to defy each other's physiological actions with differential effects , The Hedgehog Hh signaling pathway has been studied extensively in the past as an essential pathway dictating the initiation, progression and metastasis of cancers, although more recently the focus on this pathway is toward it being at essential crossroads as part of the BC stem cell circuit of pathways Although the stem cell biomarker CD has not been clearly defined, it is a moiety that binds cholesterol and has a prominent role in Hedgehog Hh signaling There are several other transcription factors and proteins that determine cancer progression in the face of ongoing endocrine therapies, some known and many unknown.

Metabolic and oxidative stress are a few of the other factors affecting endocrine resistance. The mechanisms are elucidated in detail below for each of these factors. Recent publications have demonstrated that homeostasis in cell metabolism and cell proliferation is mediated by a few other transcription factors and pathways as well. Another mechanism for endocrine resistance that has been suggested relates to the ability of the metabolic enzymes to deliver the active compound.

Some studies have reported lower concentrations of BC drugs at the site of the tumor when compared to levels in the plasma and an association with poor outcomes Alternatively, a recent study demonstrated that an elevated concentration of tamoxifen metabolites at the site of the cancer, led to agonist effects Oxidative stress is caused due to an imperfect polarization of reactive oxygen species ROS vs. Although this holds true under all disease states that progress toward chronic disorders, it stands out as a cause of major concern in cancers, where there is excess cellular mass burden.

A recent study, demonstrated the possibility of using concentrations of urinary 8-oxodG as a marker to define early stage breast cancer patients Again, a study of serum levels of 8-oxodG, indicated an association with ductal carcinoma A study revealed that E2 led to an increase in ROS production and an upregulation in the expression of genes involved in oxidative stress, e.

An association with c-SRC phosphorylation was observed in this experimental setting and it was attributed to the oxidative stress induced by E2 In luminal B breast cancer, the loss of sirtuin proteins, particularly SIRT3, promotes tumorous phenotypes dictated by atypically regulated protein acetylation and thus cells are exposed to oxidative stress. One of the analysis from the loss of SIRT3 showed its association with the development of endocrine resistance in the luminal B BC Tamoxifen builds up in tumors as part of the daily dosage regimen, and leads to an increase in tamoxifen induced oxidative stress.

This effect leads to an activation of the protein, Nuclear factor-erythroid 2-related factor-2 Nrf2 which subsequently activates the anti-oxidant response element ARE. These markers could also be studied for their role in endocrine resistant BC and also provide a rationale to study the role of oxidative stress. The plasma half-life is dictated by the metabolic rate and subsequent elimination of the drug from the plasma.

Interestingly, the potency of its active metabolite endoxifen is far more effective than tamoxifen in its native form. Differences in the expression and associated mutations in each enzyme CYPs, UGTs, or SULT's of the tamoxifen metabolic pathway, would help define the effectiveness of the drug in the individual, leading to the well-known concept of personalized medicine.

One of the crucial CYP genes, CYP2D6, has several polymorphisms within its gene, and each have been associated with either an increase or decrease in enzyme activity. Each variant defines the metabolic rate of tamoxifen, denoted as either extensive EM , intermediate IM , or poor metabolizers PM , Studies have reported altered plasma concentrations which correlate to polymorphisms in CYP2D6 The variation between activities of the CYP2D6 gene due to allelic variants across various ethnicities becomes imperative when translating preclinical data into clinical use for dosage and regimen , Along with the genotype and associated polymorphisms, the enzymes metabolize other drugs too, and thus the effectiveness of tamoxifen is dependent on the intake of tamoxifen and any other drug taken simultaneously, for example paroxetine A phase I trial conducted using Z-endoxifen as a treatment of choice rather than tamoxifen was performed to bypass the metabolism of the drug and thus differential effects due to the CYP and other enzymes, showed promising anti-tumor effects unaffected by toxicity The complicated crosstalk between the cancer cells and immune cells at the site of the tumor has led researchers to harness the unique capability of the immune system to destroy and at times shrink the size of the tumor.

In BC as in other cancers, increased levels of immune cells and soluble mediators like cytokines and some chemokines, predict poor prognosis. It has been reported that tumor associated macrophages TAM are associated with low survival rates and that the TAMs exhibit features that promote angiogenesis, migration, EMT and metastasis by suppressing anti-cancer immunity , Although in BC it is the negligible immunogenicity of the tumors that limits the effectiveness of immunotherapies like checkpoint inhibitors, yet the immune system plays an essential role in the development and branching of ductal and luminal epithelial differentiation , The cluster of genes expressed were suggestive of infiltrating immune cells and these are associated with poor response to endocrine therapy.

The myeloid derived suppressor cells MDSCs are another set of myeloid derived cells that have revealed their importance in promoting resistance to therapies Therapies involving the immune system hold promise for future efforts to overcome BC endocrine resistance. Aberrant expression of specific miRNAs has been implicated in the development of tamoxifen resistance.

Gene expression profiling has identified differential expression of miRNA expression profiles between tamoxifen resistant and sensitive BC cell lines — The miRa regulates tumor suppressor genes within the PI3K and cell cycle proteins conferred endocrine resistance The miRa, promotes endocrine resistance through a reduction in autophagosomes They typically home into specific recipient cells where they can trigger a separate cascade of molecules and associated pathological response , An analysis of the contents within the EV could shed light on their role in endocrine resistance and metastasis.

Cancer biomarkers identified include HER2 and HLA-G, which is associated with circulating tumor cells and promotes proliferation, therapy resistance and metastasis The translational capacity of miRNAs and EVs hold promise toward identifying therapies to combat endocrine resistance. The molecular mechanisms underlying resistance to endocrine therapy have been much studied and these studies have provided novel insights and yielded potentially new therapeutic strategies that may overcome endocrine resistance in BC.

While an improvement in the quality of life and survival of women with BC has increased with the discovery of novel ER targeted therapies, endocrine resistance still remains at large. The ER signaling pathway represents a complex cascade of events with several regulators and comprehensive crosstalk with and between pathways, thereby resulting in the emergence of endocrine resistance.

The authors view stem cells and the immune system as a focus toward all future studies on overcoming endocrine resistance in BC and other solid cancers. The soluble microenvironment around the BC, which consists of hormones, growth factors, cytokines, ROS, and various other types of metabolic compounds determine the effectiveness of the immune system in eliminating or shrinking the size of tumors. The upcoming efforts should now be to study potential biomarkers for definitive use in the clinic in greater detail.

It is well-understood that results that appear promising in cell lines will not entirely translate into clinically reproducible results, thereby rendering clinical validation as a necessary step in evaluating novel therapeutic strategies. A focused study of the immune cell infiltrates and tumor spatial architecture around the site of the cancer, polymorphisms within metabolic enzymes and oxidative stress milieu are also aspects that will help clinicians in treatment decisions. This approach will help identify novel mediators, molecules and pathways of interest thereby resulting in tailor-made treatment for different sets of patients with similar clinical symptoms and molecular profiles.

All authors contributed to the text and design of the review and approved the final manuscript. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. We thank Dr. Lesley-Ann Martin who had helped with discussions and Aidan M. Murphy who proof read and edited the review for better readability.

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