Estrone
Introduction
Section titled “Introduction”Estrone (E1) is a crucial estrogen hormone, playing a significant role in human physiology, particularly in postmenopausal women. Along with estradiol (E2), estrone is one of the two primary active estrogens, though E1 is typically more abundant in postmenopausal individuals, a demographic with the highest incidence of breast cancer.[1]The understanding of estrone’s levels and its metabolic pathways is essential due to its involvement in various biological processes, including the growth and proliferation of mammary tissue and estrogen-receptor positive (ER+) breast cancer.[1]
Biological Basis
Section titled “Biological Basis”Estrone exerts its effects by activating estrogen receptors (ER), thereby potentiating estrogenic responses such as the growth and survival of hormone-responsive breast cancer cells.[1] While E1 itself is active, its effects can also be driven by its conversion to E2 via 17-beta-hydroxysteroid dehydrogenase, given E2’s significantly higher affinity for ER.[1]The plasma concentrations of estrone are primarily influenced by two major biochemical reactions. First, the enzyme aromatase (CYP19A1) catalyzes the synthesis of E1 from androstenedione.[1] Second, steroid sulfatase (STS) facilitates the hydrolysis of estrone conjugates (E1Cs), which include both sulfate and glucuronide forms, with estrone sulfate being the predominant conjugate.[1] Notably, STSis expressed in breast cancer tissues, where its activity can even surpass that of aromatase.[1]Genetic factors significantly contribute to individual variations in circulating estrone concentrations. Polymorphisms in genes such asCYP19A1, ESR1, and SHBGhave been shown to influence estrogen levels.[2]Genome-wide association studies (GWAS) have identified specific single nucleotide polymorphisms (SNPs) associated with variations in plasma E1C and the E1C/E1 ratio, particularly within theSLCO1B1gene, which encodes OATP1B1, a transporter for estrone sulfate.[1] For instance, the SNP rs12586722 has been associated with increased E1 concentrations.[1]
Clinical Relevance
Section titled “Clinical Relevance”Elevated estrone levels are linked to an increased risk of estrogen-receptor positive (ER+) breast cancer and can contribute to tumor progression.[1]Similarly, estrone conjugates have also been associated with breast cancer risk and progression.[1]Understanding the factors that govern individual variations in plasma estrone concentrations is therefore crucial for comprehending their role in breast cancer occurrence and recurrence.[1]Therapeutic strategies for ER+ breast cancer include the development ofSTSinhibitors, which target the synthesis of estrogens from estrone sulfate, offering an additional approach to treatment.[1]Genetic variations influencing E1C plasma concentrations and specific SNP biomarkers hold promise for identifying ER+ breast cancer patients who may particularly benefit fromSTS inhibitor therapies.[1]
Social Importance
Section titled “Social Importance”In the context of “Precision Medicine,” gaining a deeper understanding of the genetic and other factors that influence individual variations in plasma estrone levels can pave the way for more personalized approaches to the therapy and prevention of ER+ breast cancer.[1]This knowledge, when integrated with other influencing factors such as body mass index (BMI), age, and diet, contributes to a more comprehensive and individualized strategy for managing breast cancer risk and treatment.[1]
Methodological and Statistical Considerations
Section titled “Methodological and Statistical Considerations”The current research, while providing valuable insights into estrone, is subject to several methodological and statistical limitations. The study population comprised 774 postmenopausal women.[1]a cohort size that, while substantial for a targeted investigation, might limit the statistical power to detect genetic variants with small effect sizes or those with lower minor allele frequencies, especially after applying a stringent genome-wide significance threshold (p ≤ 5.0E–08).[1]This could lead to an underestimation of the full genetic landscape influencing estrone levels. Furthermore, the systematic exclusion of imputed SNPs with dosage r2 values <0.3 and/or minor allele frequency (MAF) values <0.01, along with the initial removal of reference SNPs with MAF <0.005.[1]ensures data quality but might inadvertently filter out rare variants that could have significant biological impacts on estrone pathways. Finally, the research notes a gap in previously published genome-wide association studies for plasma estrone (E1), estrone sulfate (E1S), or androstenedione in postmenopausal women.[1] indicating a critical need for independent replication in diverse cohorts to confirm the identified associations and strengthen their validity before widespread clinical application.
Cohort Specificity and Generalizability
Section titled “Cohort Specificity and Generalizability”The findings are derived from a highly specific cohort of postmenopausal women with estrogen-receptor positive (ER+) breast cancer.[1]which limits the direct generalizability of these results to broader populations. The genetic factors influencing estrone levels might differ significantly in premenopausal women, healthy individuals, or those with different breast cancer subtypes, as the biological mechanisms and hormonal milieu vary across these groups. While principal component analysis (PCA) was utilized to adjust for population substructure.[1]and ancestry-specific differences in hormone ratios were observed (e.g., African-American women showing a higher mean E1/androstenedione ratio than those of European ancestry).[1] the detailed implications of ancestry composition on specific SNP effects are not fully elucidated. For instance, the high linkage disequilibrium (R2 = 1.00) between rs10841753 and rs11045819 in populations of European descent.[1]suggests that genetic associations might exhibit variability across different ancestral groups, potentially limiting the direct applicability of these findings globally. Additionally, the estrone and estrone conjugate (E1C) levels were captured as single plasma concentrations.[1]which may not fully represent the dynamic fluctuations of hormone levels over time or capture the long-term exposure, potentially overlooking important temporal aspects of estrone regulation.
Unaccounted Environmental and Mechanistic Factors
Section titled “Unaccounted Environmental and Mechanistic Factors”Despite accounting for several important covariates such as BMI, age at diagnosis, recruitment site, smoking history, and prior hormone replacement therapy (HRT) use.[1]other environmental or lifestyle factors known to influence estrone levels, including specific dietary components or physical activity, were not explicitly detailed as covariates. The influence of these unmeasured factors could introduce residual confounding, potentially impacting the observed genetic associations or their effect sizes. Furthermore, the complex interplay between genetic predispositions and environmental exposures (gene-environment interactions) in shaping estrone levels was not a primary focus of this investigation. For instance, while diet is acknowledged as an influence on circulating estrogen concentrations.[1]specific gene-diet interactions that could modulate estrone pathways were not explored, which is crucial for a complete understanding of estrone regulation. Finally, despite the identification of several genome-wide significant and suggestive SNP signals, the precise functional consequences of some identified variants, such as the missense variantrs114864695 in ADAM21, remain unknown.[1]This highlights a critical gap in fully understanding the biological mechanisms by which these genetic variations impact estrone biosynthesis and metabolism, necessitating further functional studies to elucidate the molecular roles of these variants and their downstream effects.
Variants
Section titled “Variants”The regulation of estrone levels, a key estrogen, is a complex process influenced by a multitude of genetic factors, with variants in various genes contributing to individual differences in its circulating concentrations. These genetic variations can affect the synthesis, metabolism, transport, or signaling pathways related to estrone, ultimately impacting its physiological roles and clinical implications. Genome-wide association studies (GWAS) have identified numerous single nucleotide polymorphisms (SNPs) associated with estrone levels, providing insights into the genetic architecture of hormone regulation.[1] One of the most directly relevant genes is _CYP19A1_, which encodes the aromatase enzyme, a critical protein responsible for converting androgens into estrogens, including the conversion of androstenedione to estrone (E1).[1] Variations within the _CYP19A1_locus significantly influence circulating estrogen levels, particularly in postmenopausal women where peripheral aromatization is the primary source of estrogens.[2] For instance, the *rs17601876 * variant, located within _CYP19A1_, has been associated with an increased E1/androstenedione ratio, suggesting that its minor allele (G) may lead to enhanced aromatase activity or altered substrate availability, thus affecting estrone production.[1] Other variants like *rs2899472 * and *rs727479 * in the _CYP19A1_locus are also implicated in modulating aromatase expression or enzyme efficiency, contributing to inter-individual differences in estrone levels.
Other genetic variants influence estrone levels through diverse mechanisms, often related to transport or signaling. The_SLCO1B1_ gene encodes an organic anion transporting polypeptide, OATP1B1, predominantly expressed in the liver, which is critical for the uptake and clearance of various endogenous and exogenous compounds, including steroid conjugates like estrone sulfate.[1] The *rs10841753 * variant in _SLCO1B1_is among those identified in GWAS that show an association with plasma estrone concentrations, likely by altering the efficiency of estrone conjugate transport and subsequent metabolism.[1] Similarly, variants in _CDK14_ (Cyclin-Dependent Kinase 14), such as *rs10953024 *, and _PTPRM_ (Protein Tyrosine Phosphatase Receptor Type M), including *rs16952550 *, have shown suggestive associations with the E1/androstenedione ratio.[1] While _CDK14_ is involved in cell cycle regulation and _PTPRM_in cell adhesion and signal transduction, their influence on estrone levels may stem from their roles in broader metabolic pathways or cellular processes that indirectly impact steroid hormone synthesis or breakdown.
Further genetic insights into estrone regulation involve genes with diverse cellular functions. The_ADAM21_gene, encoding a member of the ADAM (A Disintegrin And Metalloprotease) family, is involved in cell-surface protein shedding, cell adhesion, and signaling, processes that can indirectly influence hormone bioavailability or receptor interactions.[1] The *rs12586722 * variant near _ADAM21_has been linked to increased estrone concentrations, suggesting an impact on its regulation or related pathways.[1] Other variants, such as *rs8014252 * in _ADAM21_, or those in genes like _MIR4713HG_, a long non-coding RNA, _TRIM4_ (Tripartite Motif Containing 4), involved in ubiquitin ligase activity, _GML_(Glycine Methyltransferase-Like), and_GBX2-AS1_, an antisense RNA, also contribute to the complex genetic landscape influencing estrone levels. Similarly, variants like*rs1416584 * in the _DMAC1_-_PTPRD_ region, which involves a protein tyrosine phosphatase, and *rs7105310 * in the _NAP1L1P1_-_RPUSD4_locus, potentially affecting gene expression or protein function, are part of the broader genetic factors associated with individual differences in estrone metabolism and circulating levels.[1]
Key Variants
Section titled “Key Variants”| RS ID | Gene | Related Traits |
|---|---|---|
| rs2899472 rs727479 rs17601876 | MIR4713HG, CYP19A1 | beta-amyloid 1-42 estrone heel bone mineral density body height uterine cancer |
| rs17277546 | TRIM4 | hormone metabolite serum metabolite level estrone testosterone |
| rs10093796 | GML | estrone |
| rs10841753 | SLCO1B1 | response to antineoplastic agent estrone |
| rs10953024 | CDK14 | estrone |
| rs12586722 rs8014252 | ADAM21 | estrone |
| rs1453308 rs1453307 | GBX2-AS1 | estrone |
| rs16952550 | PTPRM | estrone |
| rs1416584 | DMAC1 - PTPRD | estrone |
| rs7105310 | NAP1L1P1 - RPUSD4 | estrone |
Estrone and its Forms: Definitions and Nomenclature
Section titled “Estrone and its Forms: Definitions and Nomenclature”Estrone (E1) is a significant estrogen, particularly prominent in postmenopausal women, a demographic with a high incidence of breast cancer.[1]As one of the two major active estrogens, alongside estradiol (E2), E1 plays a crucial role in activating estrogen receptors (ER) and potentiates estrogenic effects, which include the growth and survival of hormone-responsive breast cancer cells.[1] While E1 itself contributes to estrogenic activity, its effects can also be driven by its conversion to E2 via 17-beta-hydroxysteroid dehydrogenase, given E2’s notably higher affinity for ER.[1]Related to estrone are its conjugated forms, collectively termed Estrone Conjugates (E1C). These include both sulfate and glucuronide conjugates, with estrone sulfate being the predominant form.[1]The levels of E1C in plasma are analyzed in conjunction with E1 and androstenedione, a precursor hormone involved in the steroid hormone biosynthesis pathway.[1]Understanding the interplay and concentrations of these various forms is essential for comprehending the estrogen pathway and its implications, especially in conditions such as estrogen receptor-positive (ER+) breast cancer.
and Operational Definitions of Estrone
Section titled “and Operational Definitions of Estrone”Estrone levels are precisely defined and measured as plasma concentrations of E1, E1C, androstenedione, and the ratios of E1/androstenedione and E1C/E1.[1] These values are treated as continuous quantitative variables in research, enabling detailed statistical analysis.[1]The approach involves sophisticated techniques such as gas chromatography–tandem mass spectrometry (GC-MS), which is utilized to assay concentrations of E2, E1, total E1C (including sulfate and glucuronide conjugates), testosterone, and androstenedione.[1] To ensure statistical assumptions are met, especially for genome-wide association studies (GWAS), phenotypes with skewed distributions often undergo transformations, such as Van Der Waerden transformations, to achieve a Gaussian distribution.[1] Research criteria for statistical significance in GWAS typically employ a p-value of 5.0E–08 as the threshold for genome-wide significance, with a p-value of 5.0E–06 often indicating suggestive significance.[1] These rigorous operational definitions and criteria are vital for identifying genetic associations and understanding the hormonal landscape in clinical populations.
Clinical Significance and Classification of Estrone Levels
Section titled “Clinical Significance and Classification of Estrone Levels”The clinical significance of estrone levels is particularly evident in postmenopausal women diagnosed with ER+ breast cancer, where these hormones are drivers of tumor growth.[1]Research has established associations between estrone levels and various clinical variables. For instance, both E1 and E1C, as well as the E1/androstenedione ratio, show significant positive associations with Body Mass Index (BMI).[1] Conversely, the E1C/E1 ratio does not appear to be associated with BMI.[1] Further clinical criteria reveal that age at diagnosis is positively associated with E1 and the E1/androstenedione ratio, while being negatively associated with E1C/E1.[1] Smoking status is linked to E1C concentrations, with smokers generally exhibiting lower mean E1C levels than non-smokers.[1]Similarly, women with prior hormone replacement therapy (HRT) use tend to have lower mean E1C concentrations.[1] Racial classifications, particularly African-American women, have been observed to have a higher mean E1/androstenedione ratio compared to patients of European ancestry.[1]These associations highlight the complex interplay between demographic factors, lifestyle, and estrone metabolism, suggesting that genetic variations impacting estrone conjugate plasma concentrations, such as polymorphisms inSLCO1B1, could serve as potential SNP biomarkers to identify ER+ breast cancer patients who might benefit from steroid sulfatase (STS) inhibitors.[1]
Clinical Assessment and Hormonal Profiling
Section titled “Clinical Assessment and Hormonal Profiling”The diagnostic evaluation of estrone levels involves a comprehensive clinical assessment alongside precise hormonal profiling to understand its role in health and disease, particularly in conditions like estrogen-receptor positive (ER+) breast cancer in postmenopausal women. Clinical variables such as Body Mass Index (BMI), age at treatment, smoking history, prior hormone replacement therapy (HRT) use, prior tamoxifen use, and prior chemotherapy are routinely assessed as they can significantly influence plasma concentrations of estrone (E1), estrone conjugates (E1C), androstenedione, and their respective ratios.[1] For instance, E1 and E1C have demonstrated significant positive associations with BMI, highlighting the importance of physical examination findings in the overall diagnostic picture.[1] Direct of these hormones is typically performed using gas chromatography–tandem mass spectrometry, providing continuous quantitative data on E1, E1C, androstenedione, and derived ratios like E1C/E1 and E1/androstenedione.[1]These biochemical assays are crucial for establishing baseline hormone profiles and monitoring changes that may be indicative of underlying pathological processes or responses to therapy.
Genetic and Molecular Biomarker Analysis
Section titled “Genetic and Molecular Biomarker Analysis”Genetic testing and molecular marker analysis offer a deeper understanding of individual variations in estrone metabolism and their clinical implications. Genome-wide association studies (GWAS) are employed to identify single nucleotide polymorphisms (SNPs) that significantly influence circulating estrone concentrations.[1] For instance, missense variants in the SLCO1B1 gene, such as rs4149056 and rs11045819 , have been identified as genome-wide significant signals associated with plasma E1C concentrations and the E1C/E1 ratio, respectively.[1]These genetic insights can predict an individual’s estrone pathway activity, potentially identifying ER+ breast cancer patients for whom steroid sulfatase (STS) inhibitors might offer clinical benefit by targeting the synthesis of estrogens from estrone sulfate.[1] Other genes, including CYP19A1, ESR1, SHBG, and TSPYL5, also harbor polymorphisms known to affect circulating estrogen levels, underscoring the utility of a genetic approach in understanding an individual’s risk for breast cancer occurrence or recurrence.[1]
Differential Diagnosis and Therapeutic Guidance
Section titled “Differential Diagnosis and Therapeutic Guidance”The interpretation of estrone levels within a diagnostic framework is critical for distinguishing various conditions and guiding therapeutic strategies, particularly in ER+ breast cancer. Elevated estrone is recognized as the major circulating estrogen in postmenopausal women and is known to promote the growth and proliferation of ER+ breast tumors.[1]Therefore, accurate estrone assessment, combined with an understanding of its metabolic pathways, helps differentiate between physiological variations and pathological states that necessitate intervention. The identification of genetic variations, such as those inSLCO1B1, provides potential SNP biomarkers that can inform treatment decisions, suggesting specific patients might benefit from therapies like STSinhibitors which block the conversion of estrone conjugates to active estrone.[1] This precision medicine approach aims to tailor treatments based on an individual’s unique hormonal and genetic profile, moving beyond general diagnostic criteria to more personalized and effective patient management.
Estrone Synthesis, Metabolism, and Circulating Forms
Section titled “Estrone Synthesis, Metabolism, and Circulating Forms”Estrone (E1) serves as the primary circulating estrogen in postmenopausal women and is a crucial driver for the growth and proliferation of estrogen-receptor positive (ER+) breast tumors. While E1 itself activates estrogen receptors, its effects may also be mediated by its conversion to estradiol (E2) through the enzyme 17-beta-hydroxysteroid dehydrogenase, given E2’s significantly higher affinity for ER.[1] The body produces E1 primarily through two major pathways: the aromatase (CYP19A1) catalyzed synthesis from androstenedione, which occurs in various tissues including adipose tissue, adrenal glands, the liver, and within breast tumors, and the hydrolysis of estrone-3-sulfate (E1S).[1]Estrone-3-sulfate (E1S) is a biologically inactive conjugate of E1, yet it functions as a significant reservoir for active estrogen in the body. This inactive form can be converted back to active E1 through the action of steroid sulfatase (STS).[1] In postmenopausal women, circulating E1S concentrations typically far exceed those of E1, highlighting its importance as a precursor.[1]The liver is a major site for both the sulfation of E1 to E1S and the desulfation of E1S back to E1, a dynamic intracellular cycling process believed to be vital for regulating estrogen activity.[3]
Cellular Actions and Tissue-Level Regulation
Section titled “Cellular Actions and Tissue-Level Regulation”At the cellular level, estrone exerts its influence by binding to and activating estrogen receptors (ER), thereby promoting estrogenic effects necessary for the growth and survival of hormone-responsive breast cancer cells.[1]In breast cancer tissues, the activity of steroid sulfatase (STS) is often found to exceed that of aromatase, underscoring the significant local production of active estrone from its inactive sulfate conjugate.[1]This local conversion is further supported by the observation that estrone concentrations within breast tumors are notably higher than in the plasma of postmenopausal women, suggesting an important tissue-specific regulatory mechanism.[4]The uptake of estrone conjugates (E1Cs) by breast cancer cells is facilitated by specific transport proteins, such as organic anion-transporting polypeptides (OATPs). Studies have shown that ER+ cell lines exhibit higher rates of E1C uptake and greater transport efficiency compared to normal breast cells.[5]Furthermore, in some aromatase inhibitor-resistant breast cancer cell lines, there is an upregulation of transporters likeOATP1B1, OATP1A2, OATP4A2, and OATP5A1, which allows them to preferentially proliferate in media supplemented with E1Cs.[6]This highlights the critical role of cellular transport mechanisms and local enzymatic activity in maintaining active estrogen levels within tumor environments, even when systemic production is suppressed.
Genetic Modulators of Estrone Levels
Section titled “Genetic Modulators of Estrone Levels”Circulating estrone concentrations are influenced by a complex interplay of factors, including body mass index (BMI), age, diet, and genetic predispositions.[1] Polymorphisms in genes such as CYP19A1 (aromatase), ESR1(estrogen receptor 1), andSHBG(sex hormone-binding globulin) have been previously linked to variations in circulating estrogen levels.[1]Genome-wide association studies (GWAS) have further expanded this understanding by identifying novel genetic factors influencing estrone pathways. For instance, a GWAS for estrone conjugates (E1C) identified a missense variant inSLCO1B1, rs4149056 , as a major signal, with an additional SLCO1B1 missense variant, rs11045819 , also associated with the E1C/E1 ratio.[1]Beyond direct estrone metabolism, genetic variations can impact precursor hormones like androstenedione, as seen with a SNP inEMR2/ADGRE2, rs57712673 , associated with increased androstenedione levels and decreased EMR2 expression.[1] A cluster of SNPs on chromosome 8, including rs6988985 , also showed associations with increased androstenedione, potentially impacting steroid hormone biosynthesis enzymes.[1]For estrone itself,rs12586722 in LOC105370555 on chromosome 14 was linked to increased E1 concentrations and acts as a cis-eQTL for the nearby pseudogene ADAM20P1.[1] Another SNP, rs114864695 , a missense variant in ADAM21, was also identified as a cis-eQTL for ADAM21P1 and may influence E1 levels.[1]These genetic insights highlight the intricate regulatory networks governing individual variation in plasma estrone concentrations.
Pathophysiological Relevance and Therapeutic Implications
Section titled “Pathophysiological Relevance and Therapeutic Implications”The strong positive association between elevated circulating estrone (E1) or estrone-3-sulfate (E1S) concentrations and an increased risk of breast cancer has been consistently demonstrated in epidemiological studies.[7]This link is particularly relevant in postmenopausal women, where E1 is the predominant estrogen and breast cancer incidence is highest. The ability of breast tumors, especially ER+ ones, to efficiently take up and convert inactive E1Cs back into active E1 via steroid sulfatase (STS) makes this pathway a critical mechanism for sustaining tumor growth.[1]Understanding the factors that govern individual variations in plasma estrone levels is crucial for personalized medicine approaches in breast cancer. The development ofSTSinhibitors represents a targeted therapeutic strategy for ER+ breast cancer, particularly effective when tumors rely heavily on theSTS-catalyzed pathway for estrogen production, such as in cases resistant to aromatase inhibitors.[1] The expression of STSitself is considered an independent predictor of recurrence in human breast cancer, further emphasizing its pathophysiological importance.[8] Identifying specific genetic polymorphisms, such as those in SLCO1B1, that influence estrone conjugate plasma concentrations could serve as biomarkers to identify ER+ breast cancer patients who would benefit most fromSTS inhibitor therapy.[1]
Estrone Biosynthesis and Interconversion
Section titled “Estrone Biosynthesis and Interconversion”Estrone (E1), the predominant circulating estrogen in postmenopausal women, is critically involved in the growth and proliferation of estrogen-receptor positive (ER+) breast cancer. Its plasma concentrations are primarily determined by two key metabolic processes: the synthesis from androstenedione, catalyzed by the enzyme aromatase (CYP19A1), and the hydrolysis of inactive estrone conjugates (E1Cs), particularly estrone-3-sulfate (E1S), back into active E1 by steroid sulfatase (STS).[1] This biosynthesis occurs in various tissues, including adipose tissue, adrenal glands, liver, and within breast tumors themselves.[1]The interconversion between E1 and E1S represents a crucial regulatory mechanism. E1 can be reversibly conjugated to form E1S, which is biologically inactive but functions as a significant “reservoir” for active estrogen, with circulating E1S levels being substantially higher than E1 in postmenopausal women.[3]The liver serves as a major site for both sulfation and desulfation, highlighting an intracellular cycle believed to regulate local estrogen activity.[9]Furthermore, E1 can be converted to estradiol (E2) by 17-beta-hydroxysteroid dehydrogenase, and since E2 possesses a much higher affinity for the estrogen receptor, the estrogenic effects attributed to E1 may often be mediated through its conversion to E2.[10]
Cellular Transport and Estrogen Reservoir Dynamics
Section titled “Cellular Transport and Estrogen Reservoir Dynamics”The cellular uptake and processing of estrone conjugates are vital for maintaining intratumoral estrone levels, particularly in breast cancer. Organic anion-transporting polypeptides (OATPs), such asSLCO1B1 and SLCO1B3, play a significant role in mediating the transport of these conjugates into cells.[1] Kinetic studies have revealed that ER+breast cancer cell lines exhibit considerably higher rates of E1C uptake compared to normal breast cell lines, coupled with lower Km values for OATP-mediated E1C transport, indicating a greater transport efficiency in cancerous cells.[5] This enhanced transport capability is further underscored by the upregulation of specific OATP transporters, including OATP1B1, OATP1A2, OATP4A2, and OATP5A1, observed in letrozole-resistant MCF7 breast cancer cell lines.[6] Such mechanisms allow breast tumors to effectively sequester circulating E1Cs and subsequently hydrolyze them into active E1 via STS, thereby promoting tumor growth and proliferation, even in situations of elevated plasma E1C concentrations.[6]The ability of cancer cells to efficiently take up and utilize this inactive estrogen reservoir contributes significantly to their sustained estrogenic stimulation.
Estrogen Receptor Signaling and Gene Regulation
Section titled “Estrogen Receptor Signaling and Gene Regulation”Estrogens, primarily E1 and E2, exert their biological effects by binding to and activating estrogen receptors (ER), which are ligand-activated transcription factors. This receptor activation initiates intracellular signaling cascades that ultimately regulate gene expression, driving the growth and proliferation of both normal mammary tissue and ER+breast cancer cells.[1] The differential affinity of E1 and E2 for ER means that E2, with its higher binding affinity, often mediates the more potent estrogenic responses, even if E1 is more abundant.[10]Beyond direct receptor activation, the overall flux of estrone is subject to intricate gene regulation, often involving transcription factors and feedback loops. For example, the transcription factor encoded byTSPYL5 has been shown to regulate the expression of CYP19A1, the gene encoding aromatase, in a single nucleotide polymorphism (SNP)-dependent manner.[11]This highlights how genetic variations can influence the fundamental biosynthesis pathway of estrone, impacting its availability forER signaling and downstream biological effects.
Genetic Modulators and Therapeutic Relevance
Section titled “Genetic Modulators and Therapeutic Relevance”Genetic factors significantly influence individual variations in circulating estrone concentrations. Polymorphisms in genes such asCYP19A1, ESR1, and SHBGhave been associated with altered estrogen levels.[2] Genome-wide association studies (GWAS) have identified specific SNPs that modulate these pathways; notably, missense variants like rs4149056 and rs11045819 in SLCO1B1 are associated with plasma E1C concentrations, influencing the transport and availability of these conjugates.[1] Other genetic signals, such as rs57712673 in EMR2/ADGRE2 and rs6988985 near CYP11B1, have been linked to androstenedione levels, impacting the precursor pool for estrone synthesis.[1]These genetic variations can alter enzyme kinetics, transporter efficiency, or gene expression, thereby modulating hormone flux and overall pathway activity.[1]The dysregulation of estrone pathways is a central mechanism inER+breast cancer. Epidemiological studies have consistently linked elevated circulating E1 or E1S concentrations to an increased risk of breast cancer, with E1 levels often being higher within breast tumors compared to plasma.[7] While aromatase inhibitors (AIs) target CYP19A1 to reduce E1 synthesis from androgens, STSactivity in breast cancer frequently surpasses that of aromatase, creating an alternative, uninhibited source of active E1 from the abundant E1S reservoir.[1] This makes STS a critical therapeutic target, and STS inhibitors have been developed to block this pathway. Genetic biomarkers, such as polymorphisms in SLCO1B1, could potentially identify ER+breast cancer patients who would most benefit fromSTS inhibitor therapies.[1]
Role in Estrogen-Receptor Positive Breast Cancer
Section titled “Role in Estrogen-Receptor Positive Breast Cancer”Estrone (E1) serves as the predominant circulating estrogen in postmenopausal women and is a key driver of estrogen-receptor positive (ER+) breast tumor growth and proliferation. Elevated levels of E1 and its conjugates (E1C) are consistently associated with an increased risk of breast cancer and contribute to tumor progression, highlighting their significant diagnostic utility and role in initial risk assessment for this demographic.[1] The conversion of E1C to active E1, primarily catalyzed by steroid sulfatase (STS) within breast cancer tissue, represents a crucial pathway for local estrogenic stimulation, withSTS activity often exceeding that of aromatase. The expression of STSitself has been identified as an independent predictor of recurrence in human breast cancer, thereby indicating its prognostic value in predicting disease outcomes and progression.[1]
Genetic and Lifestyle Modulators of Estrone Levels
Section titled “Genetic and Lifestyle Modulators of Estrone Levels”Circulating estrone levels are significantly influenced by a complex interplay of genetic predispositions and various demographic and lifestyle factors, which are crucial for effective risk stratification and understanding disease associations. For example, both E1 and E1C exhibit significant positive associations with Body Mass Index (BMI), while age at diagnosis is positively correlated with E1 levels, underscoring the connections between physiological states and hormone concentrations.[1] Genetic polymorphisms in genes such as CYP19A1, ESR1, and SHBGare known to modulate circulating estrogen concentrations, contributing substantially to individual variations in hormone profiles. Genome-wide association studies (GWAS) have further identified significant genetic signals inSLCO1B1 associated with E1C concentrations, and specific polymorphisms near CYP19A1 linked to the E1/androstenedione ratio, offering critical insights for personalized risk assessment.[1]Additional factors like smoking status, prior hormone replacement therapy (HRT) use, and race also play a role in modulating estrone levels; smokers and women with previous HRT exposure tend to have lower E1C concentrations, whereas African-American women may present with a higher E1/androstenedione ratio. These diverse associations emphasize the multifactorial nature of estrone regulation and its varied implications across patient populations.[1]
Therapeutic Implications and Personalized Medicine
Section titled “Therapeutic Implications and Personalized Medicine”Given estrone’s pivotal role in driving ER+ breast cancer, its precise provides invaluable insights for guiding treatment selection and monitoring therapeutic responses. Notably, the understanding that estrone sulfate can actively contribute to cell proliferation in aromatase inhibitor (AI)-resistant, hormone receptor-positive breast cancer highlights a critical mechanism of resistance and the necessity for alternative therapeutic strategies.[6] The identification of specific genetic variations, such as SNP biomarkers within SLCO1B1 like rs4149056 and rs11045819 , holds substantial promise for advancing personalized medicine by pinpointing ER+ breast cancer patients who are most likely to benefit from steroid sulfatase (STS) inhibitors. These inhibitors offer a targeted treatment approach by blocking the conversion of estrone conjugates to active estrone, thereby providing an effective additional strategy for managing hormone-dependent cancers, particularly in cases where conventional AI therapies may be less efficacious.[1]
Frequently Asked Questions About Estrone
Section titled “Frequently Asked Questions About Estrone”These questions address the most important and specific aspects of estrone based on current genetic research.
1. My mom had breast cancer; am I more likely to have high estrone?
Section titled “1. My mom had breast cancer; am I more likely to have high estrone?”Yes, there’s a chance your genetics, inherited from your family, could influence your estrone levels. Genetic factors play a significant role in determining individual variations in circulating estrone concentrations. Elevated estrone levels are linked to an increased risk of ER+ breast cancer, so understanding your family history is important for assessing your personal risk.
2. Why do some women get breast cancer after menopause, but others don’t?
Section titled “2. Why do some women get breast cancer after menopause, but others don’t?”It’s complex, but genetic differences and individual variations in hormone levels, like estrone, contribute significantly. Estrone becomes more abundant in postmenopausal women, who also have the highest incidence of breast cancer. Your unique genetic makeup, including variations in genes likeCYP19A1 or SLCO1B1, can influence how much estrone your body produces and processes, affecting your personal risk.
3. Can my diet affect my estrone levels and breast cancer risk?
Section titled “3. Can my diet affect my estrone levels and breast cancer risk?”Yes, your diet is one of several lifestyle factors that can influence your estrone levels and, consequently, your breast cancer risk. Alongside your body mass index (BMI) and age, what you eat contributes to a more comprehensive strategy for managing breast cancer risk. Integrating this knowledge allows for a more personalized approach to prevention.
4. If my sister has high estrone, will I likely have high levels too?
Section titled “4. If my sister has high estrone, will I likely have high levels too?”Not necessarily the exact same levels, but your shared genetic background means you might have similar predispositions. Genetic factors contribute significantly to individual variations in estrone concentrations. Polymorphisms in genes likeCYP19A1, which synthesizes estrone, orSLCO1B1, which transports estrone sulfate, can run in families and influence these levels.
5. Is a genetic test useful to understand my estrone-related breast cancer risk?
Section titled “5. Is a genetic test useful to understand my estrone-related breast cancer risk?”Yes, genetic testing can be very useful for a more personalized understanding of your risk. Identifying specific genetic variations or “SNP biomarkers” can help assess your individual estrone levels and their potential link to ER+ breast cancer. This information is particularly promising for determining if you might benefit from certain targeted therapies, likeSTS inhibitors.
6. Does my body’s own enzymes affect my estrone levels?
Section titled “6. Does my body’s own enzymes affect my estrone levels?”Absolutely, your body’s enzymes are crucial for controlling your estrone levels. For example, the enzyme aromatase (encoded by theCYP19A1gene) is responsible for synthesizing estrone. Another key enzyme, steroid sulfatase (STS), helps convert inactive estrone conjugates back into active estrone, especially in tissues like breast cancer cells. Variations in these enzymes can significantly impact your estrone concentrations.
7. I’m postmenopausal; why is estrone so important for me?
Section titled “7. I’m postmenopausal; why is estrone so important for me?”Estrone becomes particularly important after menopause because it’s often the most abundant active estrogen in your body during this phase. While estradiol is also active, estrone’s levels are typically higher in postmenopausal women, a group with the highest incidence of breast cancer. Elevated estrone levels are directly linked to an increased risk of ER+ breast cancer and can contribute to tumor growth.
8. Can my genes influence how well breast cancer treatments work for me?
Section titled “8. Can my genes influence how well breast cancer treatments work for me?”Yes, your genetic makeup can definitely influence how effective certain breast cancer treatments are. Specifically, genetic variations that affect your estrone conjugate levels can help identify ER+ breast cancer patients who might particularly benefit from therapies likeSTS inhibitors. This is a key part of “Precision Medicine” to tailor treatments to your individual genetic profile.
9. Why do doctors consider my weight when discussing breast cancer risk?
Section titled “9. Why do doctors consider my weight when discussing breast cancer risk?”Doctors consider your weight, specifically your Body Mass Index (BMI), because it’s a significant factor influencing hormone levels, including estrone. Higher BMI can be linked to altered estrone metabolism and levels, which in turn are associated with an increased risk of ER+ breast cancer. Integrating this with your age, diet, and genetic factors helps create a comprehensive risk assessment.
10. Can I lower my breast cancer risk by changing my estrone levels?
Section titled “10. Can I lower my breast cancer risk by changing my estrone levels?”Yes, understanding and managing factors that influence your estrone levels can be a crucial part of lowering your breast cancer risk. Elevated estrone is linked to increased ER+ breast cancer risk and progression. Therapeutic strategies, such as developingSTSinhibitors, aim to reduce active estrone, and lifestyle factors like diet and maintaining a healthy BMI can also play a role in modulating your hormone profile.
This FAQ was automatically generated based on current genetic research and may be updated as new information becomes available.
Disclaimer: This information is for educational purposes only and should not be used as a substitute for professional medical advice. Always consult with a healthcare provider for personalized medical guidance.
References
Section titled “References”[1] Dudenkov, Tanda M., et al. “SLCO1B1 polymorphisms and plasma estrone conjugates in postmenopausal women with ER+ breast cancer: genome-wide association studies of the estrone pathway.”Breast Cancer Res Treat, vol. 169, no. 1, 2018, pp. 119-128.
[2] Haiman CA, Dossus L, Setiawan VW, Stram DO, Dunning AM, Thomas G, et al. “Genetic variation at the CYP19A1 locus predicts circulating estrogen levels but not breast cancer risk in postmenopausal women.”Cancer Res. 2007; 67(5):1893–1897.
[3] Ruder, H. J., L. Loriaux, and M. B. Lipsett. “Estrone sulfate: production rate and metabolism in man.”The Journal of Clinical Investigation, vol. 51, no. 4, 1972, pp. 1020-1033.
[4] Pasqualini, J. R., C. Chetrite, C. Blacker, et al. “Concentrations of estrone, estradiol, and estrone sulfate and evaluation of sulfatase and aromatase activities in pre- and postmenopausal breast cancer patients.”Journal of Clinical Endocrinology & Metabolism, vol. 81, no. 4, 1996, pp. 1460-1464.
[5] Nozawa T, Suzuki M, Takahashi K, Yabuuchi H, Maeda T, Tsuji A, Tamai I. “Involvement of estrone-3-sulfate transporters in proliferation of hormone-dependent breast cancer cells.”J Pharmacol Exp Ther. 2004; 311(3):1032–1037.
[6] Higuchi T, Endo M, Hanamura T, Gohno T, Niwa T, Yamaguchi Y, et al. “Contribution of estrone Sulfate to cell proliferation in aromatase inhibitor (AI) –resistant, hormone receptor-positive breast cancer.”PLoS One. 2016; 11(5):e0155844.
[7] Key, T., Appleby, P., Barnes, I., Reeves, G., Endogenous, H. “Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies.” J Natl Cancer Inst, vol. 94, no. 8, 2002, pp. 606–616.
[8] Utsumi T, Yoshimura N, Takeuchi S, Ando J, Maruta M, Maeda K, Harada N. “Steroid sulfatase expression is an independent predictor of recurrence in human breast cancer.”Cancer Res. 1999; 59(2):377–381.
[9] Raftogianis, R., C. Creveling, R. Weinshilboum, and J. Weisz. “Estrogen metabolism by conjugation.”Journal of the National Cancer Institute Monographs, vol. 2000, no. 27, 2000, pp. 24-24.
[10] Rich, R. L., L. R. Hoth, K. F. Geoghegan, et al. “Kinetic analysis of estrogen receptor/ligand interactions.”Proceedings of the National Academy of Sciences, vol. 99, no. 17, 2002, pp. 8562-8567.
[11] Liu M, Ingle JN, Fridley BL, Buzdar AU, Robson ME, Kubo M, et al. “TSPYL5 SNPs: association with plasma estradiol concentrations and aromatase expression.”Mol Endocrinol. 2013; 27(4):657–670.