High Pregnane X Receptor (PXR) Expression Is Correlated with Poor Prognosis in Invasive Breast Carcinoma

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.

Advances in drug resistance of triple negative breast cancer caused by pregnane X receptor

“…In conclusion, although PXR is mainly expressed in liver, intestinal and colon tissues, it is also expressed in normal breast tissues, and its expression level is even higher in breast cancer tissues[ 67 - 70 ]. PXR is associated with the phenotype of TNBC and is a powerful and independent poor prognostic factor[ 71 ]. PXR can accelerate the metabolism and clearance of chemotherapy drugs in TNBC through the regulation of three phases of the metabolism of chemotherapy drugs: phase I drug metabolism enzymes CYPs, phase II drug binding enzymes GSTs and UGTs, and phase III drug transporter ABCs, thus resulting in drug resistance (Table 1 ).…”

Pregnane X Receptor Signaling Pathway and Vitamin K: Molecular Mechanisms and Clinical Relevance in Human Health

“…However, prolonged PXR activation can also contribute to various diseases, including inflammatory bowel disease and cancer. Laboratory observations suggest that PXR activation by MK-4 may reduce inflammation and oxidative stress in gut epithelial cells, promoting intestinal integrity and functionality [20,[66][67][68][69][70][71]. Understanding the pivotal role of vitamin K2-mediated PXR activation is crucial for health and disease management, opening avenues for innovative therapeutic strategies.…”

“…PXR activation is crucial in controlling apoptosis and contributing to acquired resistance to chemotherapy. Moreover, high levels of PXR expression are correlated with poor prognosis in invasive breast carcinoma [71]. The suppressive role of PXR in regulating inflammatory mediators, combined with genetic polymorphisms in the PXR gene sequence, may make individuals more susceptible to developing breast cancer.…”