Steroid Hormone

Steroid hormones produced by the ovary (progestins, androgens, and estrogens) are synthesized in a sequential manner by the theca and granulosa cells of follicles (Drummond et al. 2002).

From: Comprehensive Toxicology, 2010

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Steroid hormones

J.C. Cook-Botelho, ... D. French, in Mass Spectrometry for the Clinical Laboratory, 2017

Abstract

Steroid hormones are commonly measured in patients for the diagnosis, treatment, and prevention of hormone-related diseases in men, women, and children. The methods used to measure these hormones require a large dynamic measurement range, but also in many cases need to be capable of detecting down to pg/mL concentrations. Mass spectrometry offers the capability of this measurement range and is also precise and accurate when assays are developed and calibrated correctly. However, due to the structural similarities seen between steroid hormones, it is imperative that sufficient interference testing be undertaken to ensure that no cross-reactivity exists between the different hormones in the mass spectrometry method. This chapter summarizes some key concepts that should be considered during development and validation of steroid hormone mass spectrometry assays, focusing primarily on LC-MS/MS assays.

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Steroid Hormones

Ruben Vardanyan, Victor Hruby, in Synthesis of Best-Seller Drugs, 2016

27.2 Mineralocorticoids

The mineralocorticoids [51-57] are a group of hormones that originate in the adrenal cortex. They maintain electrolyte and water balance and, in particular, control the retention of sodium and potassium in the kidneys within the body. Normally, aldosterone (27.2.1) is the only functioning natural mineralocorticoid in humans.

Aldosterone is synthesized from cholesterol. Its synthesis is stimulated principally by angiotensin II. Secreted aldosterone increases sodium retention by the kidneys. Water follows the osmotic gradient created by the sodium influx, and more water is retained. Aldosterone’s actions are mediated by binding to the mineralocorticoid receptor in target tissues, particularly in the kidney.

Other steroid hormones, such as deoxycorticosterone (27.2.2), an intermediary in the synthetic pathway of aldosterone, and cortisol, the major glucocorticoid hormone, can also bind with high affinity to mineralocorticoid receptor. However, under normal conditions, their effects on water and electrolyte balance are negligible.

Synthetic fludrocortisone (27.2.3) is the only drug available for the treatment of mineralocorticoid deficiency (Fig. 27.8.).

Fig. 27.8. Structure of mineralocorticoids.

The discovery of aldosterone in the 1950s had a profound influence on medicine. It helped to explain the mechanism of edematous states, and led to the description of the renin–angiotensin system, which regulates and controls blood pressure.

Aldosterone is now recognized as a key factor in several diseases, including hypertension, heart failure, arrhythmia, and metabolic and kidney diseases, to name only a few.

The response to aldosterone is mediated by the mineralocorticoid receptor. The classical mode of action for this receptor involves the regulation of gene transcription. Several genes have been shown to be regulated by aldosterone in epithelial tissues.

Mineralocorticoids are acutely critical for maintenance of life.

Their primary effects are increasing the reabsorption of sodium and the secretion of potassium. Secondary effects include the reabsorption of water, anion reabsorption, and secretion of hydrogen ions. The net result is maintenance of fluid and electrolyte balance and, therefore, adequate cardiac output.

A deficiency in aldosterone can occur by itself or, more commonly, in conjunction with a glucocorticoid deficiency, and is known as hypoadrenocorticism or Addison disease. A lack of aldosterone is lethal because of electrolyte imbalances and the resulting hypotension and cardiac failure. Treatment is mineralocorticoid replacement therapy, and in all cases of low aldosterone production, includes a mineralocorticoid receptor agonist, primarily fludrocortisone (27.2.3).

Aldosterone excess is most commonly observed in cases of elevated plasma potassium (hyperkalemia) and low vascular volume. Plasma potassium and angiotensin II are the major factors that regulate aldosterone secretion. Importantly, it is now recognized that approximately 10% cases of primary hypertension are associated with hyperaldosteronism, most commonly as a result of aldosterone-secreting adrenal tumors or mutations in potassium channels.

Drugs that interfere with the secretion or action of aldosterone are in use as antihypertensives.

Primary aldosteronism, which is the term used for overproduction of aldosterone by the adrenal, is treated with a glucocorticoid dexamethasone (27.1.6), which has no mineralocorticoid receptor binding capacity, but suppresses synthesis of aldosterone and endogenous production of glucocorticoids.

Treatment of increased mineralocorticoid activity usually starts with spironolactone (27.2.4), which inhibits binding of the excess cortisol to the mineralocorticoid receptor.

Another important mineralocorticoid antagonist is eplerenone (27.2.5) (Fig. 27.9.).

Fig. 27.9. Structure of spironolactone and eplerenone.

Mineralocorticoids are not included in the list of Top 200 Drugs by sales for the 2010s.

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Analysis, Removal, Effects and Risk of Pharmaceuticals in the Water Cycle

Guang-Guo Ying, ... Shan Liu, in Comprehensive Analytical Chemistry, 2013

1.6 Steroid Hormones

Steroid hormones can be classified into estrogens, androgens, progestogens, glucocorticoids, and mineralocorticoids (Table 3). Natural steroids mainly originated from the excretion (feces and urine) of human, livestock, and aquaculture. Some natural and synthetic steroids have also been used as pharmaceuticals in human daily life for many reasons, such as contraception and human therapy, and as growth promoters in livestock production to prevent and treat diseases, promote growth, and improve productivity [56,57]. Steroid hormones are a class of extremely active biological compounds and produce intensive effects at low doses. These steroids and their metabolites may pose high risks to aquatic organisms at very low environmental concentrations as they are constantly released into the environment [58–61].

Table 3. Physiochemical Properties of Steroids Estrogens, Glucocorticoids, Progestogens, and Androgens

Class Compound CAS No. MW Formula S (mg/L)a Log Kowb pKa Solid–Water Distribution
Matrix Kd (L/kg) Koc (L/kg) c
Androgens Androsta-1,4-diene-3,17-dione 897-06-3 284.39 C19H24O2 102 2.54 525
4-Androstene-3,17-dione 63-05-8 286.41 C19H26O2 66.0 2.76 Drummer silty clay loam 142 [47] 692
Freshwater sediment 19.3 [47]
Androsterone 53-41-8 290.44 C19H30O2 31.9 3.07 562
17α-Boldenone 27833-18-7 286.40 C19H26O2 NA NAd NA
17β-Boldenone 846-48-0 286.40 C19H26O2 117 3.05 251
5α-Dihydrotestosterone 521-18-6 290.44 C19H30O2 42.0 3.07 468
Epiandrosterone 481-29-8 290.44 C19H30O2 31.9 3.07 562
4-Hydroxy-androst-4-ene-17-dione 566-48-3 302.41 C19H26O3 NA 2.66 NA
Methyl testosterone 58-18-4 302.46 C20H30O2 51.9 3.72 Sand 4.6 [48] 372
Sandy loam 1.2 [48]
Clay 49.4–256.4 [48]
Clay loam 119.7 [48]
19-Nortestotserone 434-22-0 274.41 C18H26O2 323 2.82 145
Testosterone 58-22-0 288.43 C19H28O2 67.8 3.27 Conventionally tilled soil column 5.04–11.39 [49] 355
No-tilled soil column 5.00–13.52 [49]
Drummer silty clay loam 42.7 [47]
Freshwater sediment 4.57 [47]
Testosterone-16,16,17-d3 (IS) 77546-39-5 291.44 C19H25D3O2
17α-Trenbolone 80657-17-6 270.37 C18H22O2 NA NA Ultic hapludalfs 2.2 [50] 589
Lamellic Udipsamments 5.3 [50]
Udollic Epiaqualfs 6.3 [50]
Typic Endoaquolls 17.0 [50]
Mollic gleysol 41.1 [50]
17β-Trenbolone 10161-33-8 270.37 C18H22O2 NA NA Ultic Hapludalfs 4.7 [50] 1202
Lamellic Udipsamments 10.6 [50]
Udollic Epiaqualfs 14.5 [50]
Typic Endoaquolls 32.6 [50]
Mollic Gleysol 73.5 [50]
Stanozolol 10418-03-8 328.49 C21H32N2O 1.41 4.42 2291
Stanozolol-d3 (IS) 88247-87-4 331.51 C21H29D3N2O
Estrogens Estrone-2,4,16,16-d4 (ISe) 53866-34-5 274.39 C18H18D4O2
Estrone 53-16-7 270.37 C18H22O2 147 3.43 10.5 [51] ; 10.77 [52] Roseworthy Campus soil 26 [53] 1047
Roseworthy farm soil 26 [53]
Turretfield soil 54 [53]
Waite campus soil 108 [53]
Drummer silty clay loam 48.1 [47]
Freshwater sediment 3.40 [47]
17β-Estradiol-2,4,16,16-d4 (IS) 66789-03-5 276.41 C18H20D4O2
17β-Estradiol 50-28-2 272.39 C18H24O2 82.0 3.94 10.71 [52] Loamy sand 35.2 [54] 794
A light sandy loam soil 23.6–29.6 [54]
Slurry separates 372–723 [54]
Conventionally tilled soil column 13.25–19.12 [49]
No-tilled soil column 9.56–21.90 [49]
Roseworthy Campus soil 55 [53]
Roseworthy farm soil 31 [53]
Terretfield soil 50 [53]
Waite campus soil 123 [53]
Drummer silty clay loam 83.2 [47]
Freshwater sediment 3.56 [47]
17α-Ethinylestradiol 57-63-6 296.41 C20H24O2 116 4.12 10.5 [55] Roseworthy Campus soil 77 [53] 501
Roseworthy farm soil 62 [53]
Terretfield soil 78 [53]
Waite campus soil 122 [53]
Diethylstilbestrol 56-53-1 268.35 C18H20O2 3.3 5.64 11,482
Glucocorticoids Cortisol 50-23-7 362.46 C21H30O5 220 1.62 24
Cortisol-d2 (IS) 79037-25-5 364.47 C21H28D2O5
Cortisone 53-06-5 360.44 C21H28O5 297 1.81 20
Dexamethasone 50-02-2 392.46 C22H29FO5 75.1 1.72 37
Prednisolone 50-24-8 360.44 C21H28O5 221 1.40 25
Prednisone 53-03-2 358.43 C21H26O5 312 1.59 20
Progestogens Ethinyl testosterone 434-03-7 312.45 C21H28O2 74.2 3.44 269
Medroxyprogesterone 520-85-4 344.54 C22H32O3 22.2 3.50 692
19-Norethindrone 68-22-4 298.42 C20H26O2 118 3.99 224
Norgestrel 6533-00-2 312.45 C21H28O2 35.8 3.48 427
Progesterone 57-83-0 314.47 C21H30O2 5.0 3.67 2884
Progesterone-d9 (IS) 15775-74-3 323.52 C21H21D9O2
a
Solubility, calculated based on EPI Suite from the US EPA.
b
Kow octanol–water partition coefficient, calculated based on EPI Suite from the US EPA.
c
Koc, the organic carbon partition coefficient, calculated based on EPI Suite from the US EPA.
d
Not available.
e
IS, internal standard.
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Advances in Clinical Mass Spectrometry

D. French, in Advances in Clinical Chemistry, 2017

5.3 Steroid Hormones

Steroid hormones are, analytically, one of the most challenging groups of compounds to analyze in the clinical chemistry laboratory. They are formed from a common cholesterol precursor and can vary from each other by just the position of a hydroxyl group, making analysis by both immunoassay and MS challenging. Further, some of these hormones, such as testosterone and estradiol, are found at extremely low concentrations in patient serum (ng/dL or pg/mL concentrations, respectively). Steroid hormones are most commonly measured clinically in serum, urine, and saliva [99–101].

Steroid hormones have been analyzed for clinical purposes by a number of methodologies historically. First, they were measured by GC-MS, then radioimmunoassay, followed by a return to GC-MS, automated immunoassay, and finally more recently, LC-MS/MS. The steroid hormone pathway was first elucidated by GC-MS analysis; however, in the advent of radioimmunoassay, analysis became more sensitive, although the sample preparation remained similar, and a number of laboratories began using this technology instead [102,103]. However, the use, and disposal, of radioactive material made this technology cumbersome and so some clinical laboratories moved to, or back to, GC-MS analysis [102,103]. When automated immunoassay instruments were introduced into the clinical laboratory, steroid hormone assays using this technology were also developed. The advantage of the immunoassay was that no sample preparation was required, and patient serum samples could just be placed on the instrument [102,103]. However, it was soon discovered that due to the lack of sample preparation and the cross-reactivity of the antibodies in these assays for similarly structured compounds, they were not as specific and sensitive as radioimmunoassays or GC-MS. This was illustrated in a number of published papers, and one example is dehydroepiandrostenedione sulfate cross-reacting in immunoassays designed to detect only testosterone [102–106].

Before steroid hormones can be analyzed by GC-MS, serum, urine, or saliva samples have to be extracted (commonly by LLE) and derivatized in order to make them more volatile and to increase the thermal stability [107]. This adds time and cost to the method, but increases both sensitivity and chromatographic resolution [107]. However, using LC-MS/MS, the steroid hormones no longer need to be derivatized (although derivatization can still be utilized to increase sensitivity) [108,109] and can be analyzed as the native hormone after sample extraction commonly via LLE, SLE, or SPE [20,22,110]. This simplifies the sample preparation process enabling a higher sample throughput.

Currently, LC-MS/MS is utilized in a number of clinical laboratories for steroid hormone analysis [20,22,111–113]. An advantage of using MS to measure steroid hormones is the capability of quantifying multiple steroid hormones in one injection as opposed to requiring a distinct immunoassay for each hormone [111,114], although care has to be taken to chromatographically separate analytes that are isomers with the same SRM transitions, for example, testosterone and dehydroepiandrosterone (Fig. 5). Further, in certain clinical situations, MS is the only way to measure steroid hormones such as when patients are taking metyrapone and clinicians want to know their cortisol concentration, or if dexamethasone and cortisol concentrations are to be measured in patients who are undergoing a dexamethasone suppression test [114,115]. Cortisol precursors that result from use of metyrapone will cross-react with cortisol immunosassays and dexamethasone is not currently available by automated immunoassay [115,116].

Fig. 5. An extracted ion chromatogram from SRM analysis of the common testosterone transitions 289/97 and 289/109. Dehydroepiandrosterone and epitestosterone share these transitions and have to be chromatographically separated from testosterone in order to be quantified independently.

An important consideration for analysis of testosterone by LC-MS/MS is the use of gel-containing blood collection tubes. The gel in clot activator tubes that are currently available causes interfering peaks in the commonly monitored SRM transitions for testosterone that can falsely elevate the testosterone concentration, especially at low testosterone concentrations (Fig. 6A) [20,117,118]. One way to ensure that the gel does not interfere with testosterone quantification is to chromatographically separate the interfering peak from the testosterone peak via the LC method. One study showed that this was possible in a 7-min LC run time [20]. Further, the length of time that the serum sits on the gel before it is aliquoted has a significant impact on the size of the interfering peak; the longer the serum sits on the gel, the larger the interfering peaks [117].

Fig. 6. The extracted ion chromatogram for testosterone transition 289/97 can be seen in a red top tube (left hand panel) and gold top tube (right hand panel) extracted using LLE (A) run without differential ion mobility spectrometry and (B) run with differential ion mobility spectrometry.

A technique that has recently aided in analysis of steroid hormones is differential mobility spectrometry (DMS), a form of ion mobility spectrometry. This technique is not new, but until recently, it has not been used in clinical laboratories. It adds another layer of selectivity to LC-MS/MS analysis following sample introduction and atmospheric pressure ionization but before the ions enter the MS. This technique functions by separating analyte ions of interest from interfering ions based upon ion mobility. This occurs through application of high and low electric fields, and a compensation voltage that is optimized for the analyte of interest so that these analyte ions enter the MS, while interfering ions are deflected [119,120]. This application is particularly useful in steroid analysis due to the similarity in structure between these analytes, the presence of isomers, and the fact that many steroids share common fragment ions which can cause interference in quantification [119–122]. These potential interferences can therefore be preseparated by DMS before they enter the MS. DMS could also increase the sensitivity of the analysis of low concentration steroids such as estradiol and testosterone by reducing matrix interferences (although the overall signal is reduced), and potentially reduce the need for the extensive sample preparation that is often utilized in steroid hormone analysis, such as LLE [120]. Use of DMS can also alleviate the interference in testosterone methods from gel-containing sample collection tubes which simplifies data analysis for clinical laboratory staff and allows the laboratory to accept the commonly used gold top tubes for testosterone analysis (Fig. 6A and B).

Although HR-MS analysis of steroid hormones is not commonly applied in the clinical laboratory, this type of MS would simplify analysis of steroid hormones whose structures only differ slightly [4,123]. Any change in molecular formula would enable the HR-MS instruments to detect the analytes independently, and if fragmentation is not used, then the common fragment ions would not be able to cause interference as they can potentially do in LC-MS/MS analysis [4,123]. The limitations of using HR-MS are that the current sensitivity may not be sufficient for low concentration steroid hormones such as estradiol and testosterone in certain patient populations, and the dynamic range is limited which may impact the ability of one method to detect steroid hormones in multiple different patient populations [4]. Further, isomeric compounds would still require LC separation before they enter the MS [4].

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Anticancer Drugs That Modulate Hormone Action

Carmen Avendaño, J. Carlos Menéndez, in Medicinal Chemistry of Anticancer Drugs (Second Edition), 2015

1 Introduction

The recognition during the 1970s that breast and prostate tumors are subject to hormonal regulation provided the first opportunity for a targeted approach to cancer chemotherapy. Indeed, hormones, and in particular steroid hormones, are the main determinants in the induction and growth of several types of tumors, and for this reason the search for antihormones has been one of the mainstays of cancer chemotherapy. Thus, compounds acting on estrogen and androgen receptors are involved in the treatment of breast and prostatic cancers, among others, whereas corticosteroids are employed in myelomas and lymphomas because of their role in the function of lymphoid tissues.

Steroid hormone receptors are ligand-dependent transcription factors that regulate the transcription of their target genes in a highly complex process. These receptors are cytoplasmic or nuclear proteins that have a binding site for a particular steroid molecule. The steroid–receptor complexes form homodimers that bind to DNA sequences, their response elements, which are part of a gene promoter. This binding activates or represses the gene controlled by that promoter. The steroid hormone receptors consist of at least three domains:

1.

One responsible for binding the hormone.

2.

A zinc finger domain needed for DNA binding to the response element. A zinc finger can be defined as a protein structural motif characterized by a fold stabilized by coordination of an amino acid, usually cysteine or histidine, with a zinc ion. Zinc fingers typically act as protein–DNA binding elements.

3.

Finally, a domain needed for the receptor to activate the promoters of the genes being controlled.

As shown in Figure 3.1, the sequence of events leading to the start of gene transcription by a steroid hormone is as follows: (1) binding of the hormone to the receptor; (2) formation of a homodimer from two molecules of receptor; (3) transport to the nucleus, if necessary (e.g., in the case of glucocorticoid hormones); (4) binding to the response element; (5) recruitment of coactivators; and (6) final activation of transcription factors to start transcription. The ultimate consequence is the synthesis of a molecule of mRNA and the corresponding protein, which triggers the observed biological response (see also Figure 3.14a).

Figure 3.1. Sequence of events associated with steroid hormone activity. The structure of the estrogen receptor bound to DNA was generated from Proten Data Bank, reference 1HCQ and displayed with Chimera 1.8.1.

Figure 3.14. Events following the interaction of the estrogen receptors with agonists (a), modulators (b), and antagonists (c).

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Reproductive Toxicity of Organophosphate and Carbamate Pesticides

SURESH C. SIKKA, NILGUN GURBUZ, in Toxicology of Organophosphate & Carbamate Compounds, 2006

2 ALTERED HORMONE STORAGE AND/OR RELEASE

Steroid hormones do not appear to be stored intracellularly within membranous secretory granules. For example, testosterone is synthesized by the Leydig cells of the testis and released on activation of the LH receptor. Thus, compounds that block the LH receptor or the activation of the 3′,5′-cyclic AMP-dependent cascade involved in testosterone biosynthesis can rapidly alter the secretion of this hormone. The release of many protein hormones is dependent on the activation of second messenger pathways, such as cAMP, phosphatidylinositol 4,5-bisphosphate (PIP2), inositol 1,4,5-trisphosphate (IP3), tyrosine kinase, and intracellular calcium [Ca2+]i. Interference with these processes will alter the serum levels and bioavailability of many hormones.

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Reproductive and Endocrine Toxicology

R.K. Gupta, ... H.H.-C. Yao, in Comprehensive Toxicology, 2010

11.30.3.1 Transgenic Models that Affect Steroidogenesis

Steroid hormones play essential roles in the maintenance of reproductive capacity and secondary sex characteristics (Hirshfield 1991; Richards 1994). Steroid hormones produced by the ovary (progestins, androgens, and estrogens) are synthesized in a sequential manner by the theca and granulosa cells of follicles (Drummond et al. 2002). Several recent studies have used transgenic mouse models to examine the roles of genes in the steroidogenic pathway. For example, mice deficient in StAR, the cholesterol transporter on mitochondrial inner membrane, display a phenotype that closely mimics that of patients with congenital lipoid adrenal hyperplasia, an autosomal recessive disorder in which patients have impaired adrenal and gonadal steroidogenesis (Miller 2005). Studies using StAR knockout (StARKO) mice reveal that after birth the animals fail to grow and die within 1–2 days due to adrenocortical insufficiency (Caron et al. 1997). Further studies show that when StARKO mice are treated with corticosteroids to keep them alive into adulthood, their ovaries have impaired folliculogenesis (Hasegawa et al. 2000). Taken together, these studies indicate that StAR deficiency has direct consequences on the steroidogenic capacity of the ovary (Caron et al. 1997; Hasegawa et al. 2000).

Another transgenic mouse model that can be used to study steroid production is the CYP19 (Arom) KO model. Aromatase knockout (ArKO) mice, which lack the capacity to produce estrogens, are infertile due to impaired folliculogenesis at the antral stage and an inability to ovulate (Fisher et al. 1998). In addition, the antral follicles in ArKO ovaries become hemorrhagic and cystic with advancing age (Britt et al. 2000). The follicular defects in ArKO mice may result from abnormal levels of hormones including FSH, LH, E2, and testosterone (Britt et al. 2001).

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Steroid/Thyroid Hormone Receptors

R.D. Ward, N.L. Weigel, in Encyclopedia of Biological Chemistry (Second Edition), 2013

Abstract

Steroid and thyroid hormones are important in regulating a wide variety of normal physiological processes, including development, metabolism, and reproduction. The receptors for these hormones are members of the nuclear receptor superfamily of ligand-activated transcription factors. For the most part, each hormone interacts with a unique receptor, although the receptor may have multiple forms derived from the same gene by various mechanisms. Exceptions include estradiol, which activates two receptors derived from independent genes, estrogen receptor α (ERα) and ERβ, thyroid hormone receptors (TRα and TRβ), and retinoic acids, which activate the retinoic acid receptors (α, β, and γ). In response to their cognate hormones, nuclear receptors bind to specific DNA sequences altering transcription. In addition to their best-characterized actions as DNA-binding transcription factors, the receptors also influence transcription and resulting cell function through direct interactions with other transcription factors, as well as through alterations in cell signaling. These functions and the structures of the receptors are described in this article.

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Mismatch Repair Proteins in Recurrent Prostate Cancer

John Jarzen, ... Karin D. Scarpinato, in Advances in Clinical Chemistry, 2013

5 MMR Proteins: Role in Treatment Response?

Unlike mutations in other DNA repair genes that generally increase sensitivity to drug treatment, based on the fact that DNA damage remains unrepaired, defects in MMR genes often confer resistance to cancer therapy. This difference can be attributed to the contribution of MMR proteins to the initiation of apoptosis in response to DNA damage. Little is known about the involvement of MMR gene defects in treatment response to prostate cancer, in particular, since chemotherapy is generally not the first line of treatment. A few isolated cases have been reported in which MMR deficiency causes resistance or hypersensitivity to certain drugs.

Treatment with the nonsteroidal antiandrogen Bicalutamide causes a decrease in MSH6, PMS1, and PMS2, which suggests that cells become hypermutable after treatment, thus increasing the risk for resistance and androgen depletion [85]. MSI positive prostate cancer cell lines are hypersensitive to the DNA double-strand break causing agent bleomycin, which has been attributed to a combinatorial effect of mutations in several DNA repair genes [86].

Yang et al. described higher sensitivity of MMR-deficient prostate cancer cell lines to the calcium channel blocker carboxyamidotriazole and nifedipine, but not 5-FU, which was specific for an increase in apoptosis without affecting checkpoint control, suggesting that this response is independent of MMR proteins [87].

One report provided some evidence on the direct involvement of MMR proteins in an apoptotic event. It stated that MLH1 is proteolytically cleaved by caspase-3 in prostatic adenocarcinomas, which promotes DNA damage-induced apoptosis and may play an important role in apoptosis [88].

5.1 Hormone dependence

Steroid hormones promote cell growth and can promote carcinogenesis and cancer progression via binding to specific steroid receptors. Hormone deprivation is therefore a common line of treatment in prostate cancer. However, many tumors develop hormone independence, which presents a significant clinical problem. Understanding hormone independence is important for the development of effective treatments. A few reports suggest a role for MMR proteins in developing androgen independence. An early study suggested that MSI was associated with androgen receptor mutations [51]. In a small study, length variations in the AR gene were found in tumors with MSI; however, these variations did not result in the hormone refractory state [89]. Martin et al. suggested a potential involvement of MMR defects in the transition to hormone independence, similar to that found for breast cancer [81]. Reduced MSH2 expression was correlated with a hormone-sensitive phenotype and correlated with improved disease outcome and more favorable prognosis.

In turn, the hormone estrogen upregulates MMR activity in endometrial glandular cells [90]. If MSH2 is upregulated due to increased proliferation, this would increase estrogen concentrations and additionally increase proliferation. Estrogen also stimulates MLH1 expression, which may have an impact on breast cancer, a type of cancer closely related to prostate cancer [91].

Elevation of PMS2 has also been reported in prostate cancer as an independent predictor for recurrence after surgery [82], which suggests a potential role of this protein in the transition to hormone independence.

It remains to be determined what the role of MMR defects or protein elevation will be in the transition of tumors to hormone independence.

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Cellular and Molecular Toxicology

S. Safe, ... G. Chadalapaka, in Comprehensive Toxicology, 2010

2.31.4.1 Multiple Pathways for ER Activation

Steroid hormones induce their responses through interactions with their corresponding receptors which in turn interact with their cognate response elements in target gene promoters. Each hormone binds its own receptor with high specificity and has minimal affinity for other steroid hormone receptors (Nilsson and Gustafsson 2002; O’Malley 2005). However, the simple mechanism of action envisioned for ligand-activated nuclear receptors (including steroid hormone receptors) and this is exemplified by the high complex mechanisms of gene activation and repression induced by E2. For example, E2 can activate genes containing not only a consensus palindromic estrogen responsive element (ERE, GGTCA(N)3TGACC) but also promoters containing a variety of nonconsensus ERE or even ERE half-sites (Hyder et al. 1995). Moreover, several other mechanisms of ER-mediated gene expression have been identified and these include: (1) DNA-bound ER interacting with other DNA-bound transcription factors such as specificity proteins (Sp); (2) DNA-independent pathways in which ER interacts with other DNA-bound transcription factors such as Sp proteins, AP-1, GATA, and NFκB; and (3) extranuclear activation of ER (membrane and/or cytosolic) resulting in enhanced kinase signaling (Figure 3) (Blobel and Orkin 1996; Paech et al. 1997; Webb et al. 1999; Kalaitzidis and Gilmore 2005; Safe 2001; Watson et al. 2002). Thus, the simple mechanism of ER signaling has been greatly expanded to include multiple nuclear and extranuclear pathways.

Figure 3. Multiple mechanisms of ER-dependent activation of genes (top) and domain structures of ERα and ERβ (bottom).

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