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1.
Clin Proteomics ; 19(1): 14, 2022 May 14.
Artículo en Inglés | MEDLINE | ID: mdl-35568821

RESUMEN

BACKGROUND: Accumulating evidence suggests that the androgen receptor (AR) and its endogenous ligands influence disease progression in breast cancer (BCa). However, AR-mediated changes in BCa differ among the various BCa subtypes according to their hormone receptor profile [i.e., presence/absence of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2, (HER2)]. Thus, we explored the androgen-regulated transcriptomic changes in the ER+PR+HER2+ BCa cell line, BT-474, and compared them with PR-mediated changes. METHODS: We performed RNA sequencing analysis in treated BT-474 cells with dihydrotestosterone (DHT) and progesterone. Validation of the top ten differentially androgen-regulated genes and a number of other genes found in enriched signaling pathways was performed by qRT-PCR in BT-474 and other BCa cell lines. In addition, a parallel reaction monitoring targeted proteomic approach was developed to verify selected transcripts at the protein level. RESULTS: In total 19,450 transcripts were detected, of which 224 were differentially regulated after DHT treatment. The increased expression of two well-known androgen-regulated genes, KLK2 (p < 0.05) and KLK3 (p < 0.001), confirmed the successful androgen stimulation in BT-474 cells. The transcription factor, ZBTB16, was the most highly upregulated gene, with ~ 1000-fold change (p < 0.001). Pathway enrichment analysis revealed downregulation of the DNA replication processes (p < 0.05) and upregulation of the androgen signaling and fatty acid metabolism pathways (p < 0.05). Changes related to progesterone treatment showed opposite effects in gene expression than DHT treatment. Similar expression profiles were observed among other BCa cell lines expressing high levels of AR (ZR75.1 and MBA-MB-453). The parallel reaction monitoring targeted proteomic analysis further confirmed that altered protein expression (KLK3, ALOX15B) in the supernatant and cell lysate of DHT-treated BT-474 cells, compared to control cells. DISCUSSION: Our findings suggest that AR modulates the metabolism of BT-474 cells by affecting the expression of a large number of genes and proteins. Based on further pathway analysis, we suggest that androgen receptor acts as a tumor suppressor in the BT-474 cells.

2.
Crit Rev Clin Lab Sci ; 56(3): 200-223, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30821186

RESUMEN

Breast cancer (BCa) is the second most common cancer worldwide and the most prevalent cancer in women. The majority of BCa cases are positive (+) for the estrogen receptor (ER+, 80%) and progesterone receptor (PR+, 65%). Estrogen and progesterone hormones are known to be involved in cancer progression, and thus hormonal deprivation is used as an effective treatment for ER+PR+ BCa subtypes. However, some ER+PR+ BCa patients develop resistance to such therapies. Meanwhile, chemotherapy is the only available treatment for ER-PR- BCa tumors. Another hormone receptor known as the androgen receptor (AR) has also been found to be widely expressed in human breast carcinomas. However, the mechanisms of AR and its endogenous androgen ligands is not well-understood in BCa and its biological role in this hormone-related disease remains unclear. In this review, we aim to address the importance of the AR in BCa diagnosis and prognosis, current AR-targeting approaches in BCa, and the potential for AR-downstream molecules to serve as therapeutic targets.


Asunto(s)
Neoplasias de la Mama , Receptores Androgénicos , Andrógenos/metabolismo , Andrógenos/uso terapéutico , Antineoplásicos/metabolismo , Antineoplásicos/uso terapéutico , Mama/química , Mama/metabolismo , Neoplasias de la Mama/química , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Descubrimiento de Drogas , Femenino , Humanos , Receptores de Estrógenos/genética , Receptores de Progesterona/genética , Transducción de Señal
3.
Mol Cell Proteomics ; 16(3): 368-385, 2017 03.
Artículo en Inglés | MEDLINE | ID: mdl-28062795

RESUMEN

Male sex predisposes to many kidney diseases. Considering that androgens exert deleterious effects in a variety of cell types within the kidney, we hypothesized that dihydrotestosterone (DHT) would alter the biology of the renal tubular cell by inducing changes in the proteome. We employed stable isotope labeling with amino acids (SILAC) in an indirect spike-in fashion to accurately quantify the proteome in DHT- and 17ß-estradiol (EST)-treated human proximal tubular epithelial cells (PTEC). Of the 5043 quantified proteins, 76 were differentially regulated. Biological processes related to energy metabolism were significantly enriched among DHT-regulated proteins. SILAC ratios of 3 candidates representing glycolysis, N-acetylglucosamine metabolism and fatty acid ß-oxidation, namely glucose-6-phosphate isomerase (GPI), glucosamine-6-phosphate-N-acetyltransferase 1 (GNPNAT1), and mitochondrial trifunctional protein subunit alpha (HADHA), were verified in vitro. In vivo, renal GPI and HADHA protein expression was significantly increased in males. Furthermore, male sex was associated with significantly higher GPI, GNPNAT1, and HADHA kidney protein expression in two different murine models of diabetes. Enrichment analysis revealed a link between our DHT-regulated proteins and oxidative stress within the diabetic kidney. This finding was validated in vivo, as we observed increased oxidative stress levels in control and diabetic male kidneys, compared with females. This in depth quantitative proteomics study of human primary PTEC response to sex hormone administration suggests that male sex hormone stimulation results in perturbed energy metabolism in kidney cells, and that this perturbation results in increased oxidative stress in the renal cortex. The proteome-level changes associated with androgens may play a crucial role in the development of structural and functional changes in the diseased kidney. With our findings, we propose a possible link between diabetic and non-diabetic kidney disease progression and male sex hormone levels. Data are available via ProteomeXchange (https://www.ebi.ac.uk/pride/archive/) with identifier PXD003811.


Asunto(s)
Nefropatías Diabéticas/metabolismo , Dihidrotestosterona/farmacología , Metabolismo Energético/efectos de los fármacos , Riñón/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Proteómica/métodos , Animales , Células Cultivadas , Citocinas/metabolismo , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/efectos de los fármacos , Glucosa-6-Fosfato Isomerasa/metabolismo , Humanos , Marcaje Isotópico/métodos , Riñón/citología , Riñón/metabolismo , Masculino , Ratones , Subunidad alfa de la Proteína Trifuncional Mitocondrial/metabolismo , Transferasas (Grupos de Otros Fosfatos Sustitutos)/metabolismo
4.
Clin Chem Lab Med ; 54(12): 1955-1961, 2016 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-27327131

RESUMEN

BACKGROUND: Infections from microorganisms and parasites have been connected with either increased or decreased cancer risk. The objective of this study was to investigate whether infection by Echinococcus granulosus is associated with cancer risk. METHODS: We assembled a pilot retrospective cohort of patients who were diagnosed as being infected by E. granulosus in Cyprus between 1930 and 2011. Age/gender-matched non-infected family members and neighbors were selected as references. Medical history was ascertained from each study subject through in-person interview. Cox proportional hazards regression analysis was performed to assess the association of being infected by E. granulosus with cancer risk. RESULTS: Individuals with prior infection by E. granulosus (n=249) were more likely to have cancer compared to those without infection (n=753), 11.65% vs. 8.37% (p=0.0492). Survival analysis also showed that subjects with prior infection had a higher risk for developing cancer. The hazards ratio (HR) was 1.595, [95% confidence interval (CI) between 1.008 and 2.525]. The risk ratio did not change significantly (HR=1.536; 95% CI: 0.965-2.445) after adjusting for gender, year of birth, smoking status, alcohol consumption, and family history of cancer. CONCLUSIONS: Our study suggests that infection by E. granulosus may increase cancer risk. If this observation can be confirmed independently, further investigation of the mechanisms underlying the association is warranted.


Asunto(s)
Equinococosis/complicaciones , Neoplasias/complicaciones , Neoplasias/parasitología , Anciano , Animales , Estudios de Cohortes , Chipre , Equinococosis/parasitología , Femenino , Humanos , Masculino , Proyectos Piloto , Análisis de Regresión , Estudios Retrospectivos , Factores de Riesgo
6.
Nat Rev Urol ; 13(10): 596-607, 2016 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-27603220

RESUMEN

Cervical-vaginal fluid (CVF) is a complex biological fluid that hydrates the mucosa of the lower female reproductive system. In-depth proteomic and biochemical studies on CVF have revealed that it contains large amounts of endogenous proteases and protease inhibitors, including an abundance of several members of the tissue kallikrein-related peptidase (KLK) family. Despite their ubiquitous presence in human tissues and fluids, KLK expression levels vary considerably, with maximum expression observed in reproduction-related tissues and fluids. The roles of KLKs in the lower female reproductive system are not fully understood. The activation of KLKs in CVF is dependent on pH and various modes of KLK regulation in the vagina exist. KLKs have been postulated to have roles in physiological functions related to antimicrobial processes, vaginal and cervical epithelial desquamation, sperm transport, and the processing of fetal membranes as observed in preterm premature rupture of membranes. Increased understanding of the functional roles of KLKs in the lower female reproductive system could lead to new diagnostic and therapeutic modalities for conditions such as vaginal infections and vaginal atrophy.


Asunto(s)
Salud Reproductiva , Calicreínas de Tejido/metabolismo , Vagina/metabolismo , Femenino , Humanos
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