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Luminal breast cancer (BrCa) has a favorable prognosis compared with other tumor subtypes. However, with time, tumors may evolve and lead to disease progression; thus, there is a great interest in unraveling the mechanisms that drive tumor metastasis and endocrine resistance. In this review, we focus on one of the many pathways that have been involved in tumor progression, the fibroblast growth factor/fibroblast growth factor receptor (FGFR) axis. We emphasize in data obtained from in vivo experimental models that we believe that in luminal BrCa, tumor growth relies in a crosstalk with the stromal tissue. We revisited the studies that illustrate the interaction between hormone receptors and FGFR. We also highlight the most frequent alterations found in BrCa cell lines and provide a short review on the trials that use FGFR inhibitors in combination with endocrine therapies. Analysis of these data suggests there are many players involved in this pathway that might be also targeted to decrease FGF signaling, in addition to specific FGFR inhibitors that may be exploited to increase their efficacy.

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In this chapter, we summarize the birth of the field of nuclear receptors. These receptors exhibit a multitude of roles in cell biology and hence have attracted a great deal of interest in the drug discovery field. It is not certain whether these receptors evolved independently or an ancestral protein acquired various functions upon binding to preexisting small molecules, ligands. Currently, members of this receptor superfamily are categorized in six groups, including "orphan receptors." Research in the area has resulted in several clinically used drugs and continues to reveal further previously unknown roles for these receptors paving the road toward more valuable discoveries in the future.

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Steroid hormone receptors have been historically considered as nuclear transcription factors. Nevertheless, in the last years, many of them have been detected in the cellular membrane. It has been postulated that their activation can induce transcription independent rapid events involving different second messengers. In addition, several novel steroid hormone receptors, showing a different molecular structure than the classical ones, have also been characterized and most of them are also located in the plasmatic membrane. This review focuses on the variety of effects initiated by glucocorticoids, mineralocorticoids, androgens, estrogens and progesterone, and the possible receptors involved mediating these effects.

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Los receptores de hormonas esteroides han sido considerados históricamente como factores de transcripción nucleares. Sin embargo, en los últimos años surgieron evidencias que indican que su activación desencadena eventos rápidos, independientes de la transcripción y que involucran a diferentes segundos mensajeros; muchos de estos receptores han sido localizados en la membrana celular. Por otra parte, se han caracterizado varios receptores de hormonas esteroides noveles, de estructura molecular diferente al receptor clásico, localizados principalmente en la membrana celular. Esta revisión enfoca los diferentes efectos iniciados por los glucocorticoides, mineralocorticoides, andrógenos, estrógenos y progesterona, y los posibles receptores involucrados en los mismos.

Steroid hormone receptors have been historically considered as nuclear transcription factors. Nevertheless, in the last years, many of them have been detected in the cellular membrane. It has been postulated that their activation can induce transcription independent rapid events involving different second messengers. In addition, several novel steroid hormone receptors, showing a different molecular structure than the classical ones, have also been characterized and most of them are also located in the plasmatic membrane. This review focuses on the variety of effects initiated by glucocorticoids, mineralocorticoids, androgens, estrogens and progesterone, and the possible receptors involved mediating these effects.

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Cell responsiveness to steroid hormones is related to the number and affinity of its receptors, thus factors affecting steroid expression will influence tissue sensitivity and functionality. The present review discusses the role of oestrogen and progesterone receptors in sheep female reproductive physiology. The mechanism of steroid hormone action in the target cell is introduced first; the tissue distribution, physiological functions and regulation of oestrogen receptor subtypes and progesterone receptor isoforms in ruminants are reported. The role of steroid receptors in target tissues (with emphasis on the uterus and pituitary gland) during different physiological events is addressed in an attempt to clarify oestrogen and progesterone actions in different developmental and reproductive stages: prepubertal period, oestrous cycle, pregnancy, post-partum period and seasonal anoestrus. The present review shows how the distinct reproductive stages are accompanied by dramatic changes in uterine receptor expression. The role of oestrogen and progesterone receptors in the molecular mechanism responsible for premature luteolysis that results in subnormal luteal function is discussed. Finally, the effect of nutrition on sex steroid receptor expression and the involvement on reproductive performance is reported.

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Many examples of reciprocal endocrine interactions between parasites and hosts have been found in insects, arthropods and mammals. Cysticercosis produced by Taenia solium metacestodes is a widely distributed parasite infection that affects the human and the pig. Taenia crassiceps experimental murine cysticercosis has been used to explore the role of biological factors involved in host-parasite interactions. We had shown that T. crassiceps cysticercosis affects the serum concentration of steroid hormones and the reproduction behavior of the male mice host. In an effort to understand the biology of the parasite, we had investigated the parasite capacity to produce sex steroids. For this purpose, T. crassiceps cysticerci were incubated in the presence of different steroid precursors. TLC and recrystallization procedures showed that testosterone is produced from 3H-androstenedione in cysticerci. The conversion of 3H-testosterone to androstenedione, although present is much less significant. In addition, we had studied the production of testosterone by T. solium cysticerci. For this purpose, cysticerci were dissected from pork meat and incubated as above described. The results showed that T. solium cysticerci also produce testosterone. We have speculated about the importance of androgens in the growth of T. crassiceps cysticerci and found that the addition of the antiandrogen flutamide to the culture media of the parasites significantly decreased 3H-thymidine incorporation. We therefore hypothesized, that the ability of cysticerci to produce testosterone from steroid precursors might be important for the parasite growth and development.

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An essential event in immune activation is the increase of cytokines in both plasma and immune tissues. Steroid hormones influence several adaptive responses in both health and disease. Cytokines and steroids have an intimate cross-communication in many systems, making possible a satisfactory adaptive response to environmental changes. The ultimate level of integration of the cytokine-steroids cross-talk is the molecular level. We have demonstrated this in four types of cross-talk mechanisms on different cells in which steroids have major roles: (1) The tumor necrosis factor (TNF)-glucocorticoid receptor (GR) transcriptional interaction in cellular targets of TNF-induced cytotoxicity. TNF potentiates the transactivation activity of GR and the priming with TNF increases the protective action of GR on TNF-induced cytotoxicity. (2) The GR-T cell receptor (TCR) antagonism in GR-TCR-induced T cell apoptosis and its modulation by cAMP. cAMP inhibits the TCR-induced apoptosis through a PKA-CREB-dependent mechanism and potentiates glucocorticoid-induced apoptosis by means of a CREB-independent mechanism. (3) The GR influence on Th1-Th2 cytokine expression and differentiation. Glucocorticoids inhibit the induction of GATA-3 and T-bet transcription factors. (4) The influence of ER/Smad-4 signaling cross-communication on prolactinoma pathogenesis. Physical and functional interactions between Smad-4 and estrogen receptors take place in prolactinoma cells, providing a molecular explanation to link the tumorigenic action of these two important players of prolactinoma pathogenesis. The molecular cross-talk between steroids and transcription factors is the mechanism that provides the basis for the outcome of adaptive responses integrating the systemic information provided by hormones and cytokines.

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Over the past few decades much effort has been expended elucidating the key domains of the nicotinic acetylcholine receptor (AChR) responsible for agonist binding, ion conduction, and gating. An emerging concept in the receptor field has been to consider the receptor entity as a signal transducer that suffers modulatory control by allosterically acting ligands. Of particular interest are the molecules that inhibit the agonist-evoked ion flux activity in a noncompetitive manner: the so-called noncompetitive inhibitors (NCIs). The actual knowledge on the action of NCIs was obtained by using several drugs from exogenous origin. However, several lines of investigation indicate that the receptor protein can be modulated by endogenous substances other than acetylcholine. In this regard, we outline the progress evidenced on the localization of binding sites for drugs of endogenous origin that have been found to directly interact with the AChR in a noncompetitive fashion. Among them we can quote lipids such as steroids and fatty acids, the neurotransmitter 5-hydroxytryptamine (5-HT) and related compounds, as well as the neuropeptide substance P. We present the available experimental evidence indicating the existence of both luminal (located into the ion channel) and nonluminal (located out of the ion channel) binding sites for endogenous NCIs. Particularly, the binding site for substance P is found in the delta M2 domain. In addition, the locus for 5-HT is putatively located in the ion channel close to the serine ring, whereas the binding site for two competitive antagonists of 5-HT receptors (e.g., methysergide and spiperone) is located closer to the external end of the ion channel. Instead, fatty acid and steroid molecules bind to nonluminal sites. More specifically, fatty acids may bind to the annular lipid domain of the AChR or/and to the high-affinity quinacrine site (a NCI from exogenous origin) which is located at a nonannular lipid domain. Additionally, steroids may bind to a site located on the extracellular hydrophilic domain of the AChR or/and at the lipid-protein interface, specifically, at the annular lipid domain and/or close to the nonannular quinacrine binding site.

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