Abstract
Pregnane X Receptor (PXR) is involved in human cancer, either by directly affecting carcinogenesis or by inducing drug-drug interactions and chemotherapy resistance. The clinical significance of PXR expression in invasive breast carcinoma was evaluated in the present study. PXR protein expression was assessed immunohistochemically on formalin fixed paraffin-embedded breast invasive carcinoma tissue sections, obtained from 148 patients, and was correlated with clinicopathological parameters, molecular phenotypes, tumor cells’ proliferative capacity, and overall disease-free patients’ survival. Additionally, the expression of PXR was examined on human breast carcinoma cell lines of different histological grade, hormonal status, and metastatic potential. PXR positivity was noted in 79 (53.4%) and high PXR expression in 48 (32.4%), out of 148 breast carcinoma cases. High PXR expression was positively associated with nuclear grade (p = 0.0112) and histological grade of differentiation (p = 0.0305), as well as with tumor cells’ proliferative capacity (p = 0.0051), and negatively with luminal A subtype (p = 0.0295). Associations between high PXR expression, estrogen, and progesterone receptor negative status were also recorded (p = 0.0314 and p = 0.0208, respectively). High PXR expression was associated with shorter overall patients’ survival times (log-rank test, p = 0.0009). In multivariate analysis, high PXR expression was identified as an independent prognostic factor of overall patients’ survival (Cox-regression analysis, p = 0.0082). PXR expression alterations were also noted in breast cancer cell lines of different hormonal status. The present data supported evidence that PXR was related to a more aggressive invasive breast carcinoma phenotype, being a strong and independent poor prognosticator.
Highlights
Several mechanisms have been proposed for Pregnane X Receptor (PXR)-mediated effects in cancer and include regulation mechanisms have been proposed for PXR-mediated effects in cancer and include regulaof genes involved in apoptosis, cell proliferation, angiogenesis, oxidative stress,stress, cell cycle tion of genes involved in apoptosis, cell proliferation, angiogenesis, oxidative cell arrest, metabolism, inflammatory response, metastasis, drug metabolism and resistance, cycle arrest, metabolism, inflammatory response, metastasis, drug metabolism and retransport, and homeostasis (glucose,(glucose, lipid, steroid)
The results of our study demonstrated that PXR expression, assessed immunohistochemically in histopathological samples of breast carcinoma patients, was correlated with crucial clinicopathological parameters for patients’ management and prognosis
PXR was detected in carcinoma tissues but occasionally in non-neoplastic cells of the breast, which is in accordance to previous studies [30,31]. These findings suggested that high PXR expression was associated with a more aggressive breast carcinoma phenotype
Summary
Pregnane X Receptor (PXR), a member of the nuclear receptor (NR) superfamily, discovered in 1998 [1], represents a modular protein sharing common regions, a highly variable N-terminal domain, a conserved DNA binding domain (DBD), an H region (H), and a C-terminal ligand-binding domain (LBD) [2,3]. PXR is mainly expressed in liver and intestine, as well as in other tissues and organs [4,5,6,7,8]. PXR, upon ligand activation, forms a heterodimer with the Retinoid X Receptor (RXR) that binds to PXR response elements, located in the 50 -flanking regions of PXR target genes, resulting in their transcriptional activation. Each of the three genes can produce different RXR isoforms through the use of alternative promoters or splice sites [9]
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