Genetic polymorphisms of ESR1, ESR2, CYP17A1, and CYP19A1 and the risk of breast cancer: a case control study from North India
Shilpi ChattopadhyaySarah SiddiquiSalman AkhtarMohammad Zeeshan NajmS. V. S. DeoN. K. ShuklaSyed Akhtar Husain
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Estrogen is a key driver of breast cancer and genes involved in its signaling and biosynthesis are crucial in breast cancer progression. In this study, we investigated the role of estrogen signaling and synthesis related genes polymorphism in susceptibility to breast cancer risk in North India population in a case-control approach. We examined the association of single nucleotide polymorphism (SNP) in estrogen receptors, ESR1 (rs2234693) and ESR2 (rs2987983); estrogen biosynthesis enzymes, CYP17A1 (rs743572); and aromatase, CYP19A1 (rs700519) with breast cancer risk. Cases (n = 360) were matched to controls (n = 360) by age, sex, ethnicity, and geographical location. Results provided evidence that all the genetic variants were significantly associated with breast cancer risk among North Indian women. Furthermore, on performing stratified analysis between breast cancer risk and different clinicopathological characteristics, we observed strong associations for menopausal status, estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) status, clinical stage, and histological grade. Our results suggest that these genes could be used as molecular markers to assess breast cancer susceptibility and predicting prognosis in North India population.Keywords:
Estrogen receptor alpha
CYP17A1
Abstract Evidence supporting a role for estrogen in male reproductive tract development and function has been collected from rodents and humans. These studies fall into three categories: i) localization of aromatase and the target protein for estrogen (ER-alpha and ER-beta) in tissues of the reproductive tract; ii) analysis of testicular phenotypes in transgenic mice deficient in aromatase, ER-alpha and/or ER-beta gene; and, iii) investigation of the effects of environmental chemicals on male reproduction. Estrogen is thought to have a regulatory role in the testis because estrogen biosynthesis occurs in testicular cells and the absence of ERs caused adverse effects on spermatogenesis and steroidogenesis. Moreover, several chemicals that are present in the environment, designated xenoestrogens because they have the ability to bind and activate ERs, are known to affect testicular gene expression. However, studies of estrogen action are confounded by a number of factors, including the inability to dissociate estrogen-induced activity in the hypothalamus and pituitary from action occurring directly in the testis and expression of more than one ER subtype in estrogen-sensitive tissues. Use of tissue-specific knockout animals and administration of antiestrogens and/or aromatase inhibitors in vivo may generate additional data to advance our understanding of estrogen and estrogen receptor biology in the developing and mature testis.
Estrogen receptor beta
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An acute injection of estradiol is known to cause a rapid redistribution of estrogen receptors in responsive cells, measurable as depletion of the cytosol receptor content with accompanying accumulation in the nucleus. We have examined the effects of progesterone on this process in the anterior pituitary and hypothalamus using an animal model in which sensitivity to steroidal feedback control of gonadotropin secretion has been defined. Ovariectomized immature rats were administered low dose estrogen replacement for 4 days. On the morning of the fifth day, groups of animals were injected according to one of the following protocols: 1) vehicle alone; 2) 5 or 10 μg estradiol; and 3) 0.8 or 3.2 mg progesterone, followed 1 h later by vehicle or 5 or 10 μg estradiol. All animals were killed 1 h after estradiol (or vehicle) injection, and levels of cytosol and nuclear estrogen receptors were measured. The only change occasioned by progesterone treatment was a decrease in anterior pituitary nuclear estrogen receptor levels. At the 5-μg dose of estradiol, 0.8 and 3.2 mg progesterone were equally effective in diminishing nuclear estrogen receptor binding. When 10 μg estradiol were used to cause receptor redistribution, only the higher 3.2-mg dose of progesterone significantly depressed nuclear receptor binding. If ovariectomized animals were maintained in the absence of estrogen replacement, progesterone at either the 0.8- or 3.2-mg dosage was completely ineffective in altering the patterns of estradiol-induced cytosol or nuclear estrogen receptor levels. The results demonstrate a tissue-specific inhibitory action of progesterone on estrogen-induced enhancement of nuclear estrogen receptor binding. This inhibition can be partially overcome by increasing the level of estrogen used to effect receptor redistribution. The requirement for maintenance of a background level of estrogen suggests that the inhibitory action of progesterone is mediated through progesterone receptor interactions. (Endocrinology113: 15, 1983)
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After 2 weeks of administration of 17β-estradiol (E2; ∼20–30 Mg E2/kg BW-day) to adult ovariectomized female rats, concentrations of circulating triglycerides were increased 3- to 4-fold with no apparent effect on serum cholesterol levels. The increase in serum triglycerides was confined to the very low density lipoprotein (VLDL) fraction. It was determined that exposure to E2 for longer than 3 days was required to elicit this response. The concentrations of cytosolic and nuclear receptors were measured by Scatchard analysis, after either 7 or 14 days of estrogen treatment. Redistribution of hepatic estrogen receptors from the cytosolic to the nuclear compartment was not observed in animals continuously exposed to estrogen, although elevations in the concentrations of triglycerides associated with VLDL were apparent at the time points examined. Previous investigations have shown that after hypophysectomy, the concentrations of hepatic estrogen receptors are significantly decreased. We have confirmed this finding and have further shown that the nuclear uptake of cytosolic receptors is less in hypophysectomized animals than in controls when evaluated in a cellfree system. Similarly, nuclear concentrations of estrogen receptors after estrogen treatment in vivo are considerably less in hypophysectomized animals than in controls. Hypophysectomy abolished the response of the liver to estrogen; concentrations of circulating triglycerides associated with VLDL were unaffected in estrogen-treated hypophysectomized animals. These findings suggest that a correlation exists between the amount of hepatic cytosolic receptors and estrogen-mediated responses of liver.
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It is a common clinical observation that stress is accompanied by dysfunction of the hypothalamic-pituitary-ovarian axis, and there is mounting experimental evidence that CRH, the principal regulator of ACTH release and the central coordinator of the stress response, is able to suppress gonadal function by inhibiting hypothalamic GnRH release. Recently, it has been shown that immunoreactive CRH, CRH messenger RNA, and CRH receptors are also present in the ovary. This prompted us to examine the role of CRH on ovarian function. To accomplish this, we studied the effects of this neuropeptide on estrogen production and cAMP intracellular content from rat granulosa and human granulosa-luteal cells. We also evaluated the activity of the enzyme aromatase by measuring the production of tritiated water from homogenates of cultured rat granulosa cells. CRH inhibited FSH-stimulated estrogen production from rat granulosa cells in a dose-dependent fashion. The maximal effect was achieved at a concentration of 10(-8) M, which suppressed estrogen production by about 30%. Low concentrations of CRH (10(-10) M), incapable of modulating maximal estrogen production in response to FSH, provoked a right-ward shift of the estrogen dose-response curve to FSH. CRH (10(-8) M) suppressed the production of tritiated water (equivalent to estrogen production) from homogenates of rat granulosa cells incubated with a half-maximal concentration of FSH. Basal estrogen production by human granulosa-luteal cells was also inhibited by CRH at a concentration of 10(-10) M. The maximal effect was achieved with a concentration of 10(-8) M, which lowered estrogen production by 25%. The CRH receptor antagonist alpha-helical CRH-(9-41) antagonized the inhibitory effect of CRH on estrogen production from rat granulosa and human granulosa-luteal cells, whereas alone it had no effect. CRH did not have any effect on the intracellular cAMP content of rat granulosa and human granulosa-luteal cells. In conclusion, these results suggest that CRH is able to suppress estrogen production from rat and human granulosa cells in vitro. This effect seems to be linked to inhibition of aromatase activity in the rat and is independent of cAMP generation. We speculate that CRH may also interfere with hypothalamic-pituitary-gonadal axis function by acting directly at the ovarian level.
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ContextEstrogen receptor antagonism by tamoxifen inhibits GH secretion in both men and postmenopausal women, suggesting that estrogen, albeit at low concentration, stimulates GH secretion. However, systemic estrogen replacement in postmenopausal women does not enhance GH secretion. To clarify the role of estrogen in mediating GH secretion, we investigated the effect of estrogen deprivation by using aromatase inhibitors.
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Evidence supporting a role for estrogen in male reproductive tract development and function has been collected from rodents and humans. These studies fall into three categories: i) localization of aromatase and the target protein for estrogen (ER-alpha and ER-beta) in tissues of the reproductive tract; ii) analysis of testicular phenotypes in transgenic mice deficient in aromatase, ER-alpha and/or ER-beta gene; and, iii) investigation of the effects of environmental chemicals on male reproduction. Estrogen is thought to have a regulatory role in the testis because estrogen biosynthesis occurs in testicular cells and the absence of ERs caused adverse effects on spermatogenesis and steroidogenesis. Moreover, several chemicals that are present in the environment, designated xenoestrogens because they have the ability to bind and activate ERs, are known to affect testicular gene expression. However, studies of estrogen action are confounded by a number of factors, including the inability to dissociate estrogen-induced activity in the hypothalamus and pituitary from action occurring directly in the testis and expression of more than one ER subtype in estrogen-sensitive tissues. Use of tissue-specific knockout animals and administration of antiestrogens and/or aromatase inhibitors in vivo may generate additional data to advance our understanding of estrogen and estrogen receptor biology in the developing and mature testis.
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Abstract Estrogen seems to promote and maintain the typical female type of fat distribution that is characterized by accumulation of adipose tissue, especially in the sc fat depot, with only modest accumulation of adipose tissue intraabdominally. However, it is completely unknown how estrogen controls the fat accumulation. We studied the effects of estradiol in vivo and in vitro on human adipose tissue metabolism and found that estradiol directly increases the number of antilipolytic α2A-adrenergic receptors in sc adipocytes. The increased number of α2A-adrenergic receptors caused an attenuated lipolytic response of epinephrine in sc adipocytes; in contrast, no effect of estrogen on α2A-adrenergic receptor mRNA expression was observed in adipocytes from the intraabdominal fat depot. These findings show that estrogen lowers the lipolytic response in sc fat depot by increasing the number of antilipolytic α2A-adrenergic receptors, whereas estrogen seems not to affect lipolysis in adipocytes from the intraabdominal fat depot. Using estrogen receptor subtype-specific ligands, we found that this effect of estrogen was caused through the estrogen receptor subtype α. These findings demonstrate that estrogen attenuates the lipolytic response through up-regulation of the number of antilipolytic α2A-adrenergic receptors only in sc and not in visceral fat depots. Thus, our findings offer an explanation how estrogen maintains the typical female sc fat distribution because estrogen seems to inhibit lipolysis only in sc depots and thereby shifts the assimilation of fat from intraabdominal depots to sc depots.
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From preliminary observations, GH-IGF-I seems to be compromised in men with aromatase deficiency. The GH deficiency (GHD) coexists paradoxically with tall stature, raising the question whether or not a true GHD is part of this rare syndrome.To evaluate the GH secretion in aromatase-deficient men, their GH response to the GHRH plus arginine (GHRH-ARG) test was compared with that of normal subjects. The effect of estrogen replacement treatment on the GH-IGF-I axis in aromatase-deficient men was evaluated before and during therapy.A case-control study was conducted.Four adult men with aromatase deficiency were compared with 12 normal subjects.We measured the GH response to GHRH-ARG in aromatase-deficient men (at baseline and during estrogen treatment) and in normal subjects. Basal serum IGF-I was measured in both patients and controls.The response of GH to GHRH-ARG was severely impaired in men with aromatase deficiency and resulted in significantly lower (P < 0.001) levels than in normal subjects. Although normal, serum IGF-I levels were also significantly lower (P < 0.001) than in normal subjects. Both GH peak and IGF-I concentrations were not modified by estrogen therapy in men with aromatase deficiency.In aromatase-deficient men, GH response to potent provocative stimuli is impaired and is not restored by exogenous estrogens. Furthermore, a tall stature may be reached, notwithstanding the coexistence of GHD, if a prolonged time for growth is available due to a delay in bone maturation, and other growth factors different from GH (mainly insulin) promote growth.
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Selective regulation of estrogen receptor (ER) content, distribution, and function has been studied in mouse mammary gland, as influenced by PRL and estradiol administration in vivo. In virgin female C3H+ mice, short-term treatment with PRL causes an apparent increase in the affinity with which activated ER binds to DNA. However, a contrasting effect of PRL to diminish nuclear accumulation of ER and progesterone receptors is consistently observed in PRL-treated mice. The ER-enhancing activity of PRL and the PRL mediation of estrogen stimulation of ER are more pronounced in C3H than in BALB/c mammary tissue, evidenced by the ability of bromocryptine (CB-154) to eradicate estrogen-stimulated appearance of ER in C3H, while having no effect on this parameter in the BALB/c animal. Uterine ER in either strain is independent of PRL and is stimulated with equivalent efficiency by estradiol. Stimulation of mammary gland ER activity by estradiol is dose responsive, being linear within the range of 0.25-5.0 /jg/kg body weight. The simultaneous rise in cytosolic progesterone receptor binding activity is also linear over the same range. With respect to PRL responsiveness, ovariectomized adult (but not immature) mouse tissue shows a doubling of ER content with 103 or 104 μg/kg body weight, but no elevation with 102 or lower levels. The upper level is approximately equivalent to that seen in the intact or estrogen-replaced castrate mouse. High levels of PRL administered to these latter animal groups cause a secondary increase in ER activity. A PRL-independent component of estradiolstimulated ER activity is demonstrable from experiments using various doses of CB-154 in animals treated with different levels of estradiol. High dosages of CB-154 superimposed on a highly inducing level of estradiol have a side effect of redistributing nuclear ER to the cytosol; sucrose gradient analyses of nuclear receptor levels demonstrate that this pharmacological action of CB-154 is not mediated through its PRL-suppressive effect. The suppression of nuclear ER by CB-154 is reflected in a loss of estrogen-induced progesterone receptor activity. The ability of tamoxifen to inhibit estrogen-stimulated progesterone receptor activity is appreciably curtailed by concomitant treatment with PRL. These results demonstrate that, of PRL and estradiol, PRL is the dominant factor in eliciting ER activity in mouse mammary gland. Basal conditions are established for quantifying the relative contributions of these and other modifiers of mammary tissue function at the molecular level, and for uncovering otherwise-masked differential dose-related effects of such agents. (Endocrinology121: 141–149, 1987)
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