LXR/RXR pathway signaling associated with triple-negative breast cancer in African American women

Abstract

BackgroundTriple-negative breast cancer (TNBC) is more prevalent in African and African American (AA) women compared to European American (EA) women. African and AA women diagnosed with TNBC experience high frequencies of metastases and less favorable outcomes. Emerging evidence indicates that this disparity may in fact be the result of the uniquely aggressive biology of African and AA disease.PurposeTo understand the reasons for TNBC in AA aggressive biology, we designed the present study to examine the proteomic profiles of TNBC and luminal A (LA) breast cancer within and across patients’ racial demographic groups in order to identify proteins or molecular pathways altered in TNBC that offer some explanation for its aggressiveness and potential targets for treatment.Materials and methodsProteomic profiles of TNBC, LA tumors, and their adjacent normal tissues from AA and EA women were obtained using 2-dimensional gel electrophoresis and bioinformatics, and differentially expressed proteins were validated by Western blot and immunohistochemistry. Our data showed that a number of proteins have significantly altered in expression in LA tumors compared to TNBC, both within and across patients’ racial demographic groups. The differentially overexpressed proteins in TNBC (compared to LA) of AA samples were distinct from those in TNBC (compared to LA) of EA women samples. Among the signaling pathways altered in AA TNBC compared to EA TNBC are innate immune signaling, calpain protease, and pyrimidine de novo synthesis pathways. Furthermore, liver LXR/RXR signaling pathway was altered between LA and TNBC in AA women and may be due to the deficiency of the CYP7B1 enzyme responsible for cholesterol degradation.ConclusionThese findings suggest that TNBC in AA women enriched in signaling pathways that are different from TNBC in EA women. Our study draws a link between LXR/RXR expression, cholesterol, obesity, and the TNBC in AA women.

Surpassing 10 000 identified and quantified proteins in a single run by optimizing current LC-MS instrumentation and data analysis strategy

“…The combined down-regulation of the LXR/RXR pathway and acute phase response signalling pathway was widely observed in proteomic studies for various cancer types, e.g. for colon adenocarcinomas, 51 for triple-negative breast cancer (in combination with a downregulation of the FXR/RXR activation pathway, 52 which was also found here) and in the urine of prostate cancer patients. 53 LXR acts as sensor for cholesterol homeostasis and in normal cells the pathway is activated by high intracellular cholesterol concentrations to reduce synthesis and influx and enhance cholesterol efflux.…”

Cholesterol, Oxysterols and LXRs in Breast Cancer Pathophysiology

“…They demonstrated that representations of LXR/RXR signaling pathways were increased in LA samples from AA women and that this pathway was altered in TNBC samples from AA women. Furthermore, they showed that Cyp7B1, the enzyme responsible for the degradation of 27OHC, had strong immunoreactivity in the tumor cells of LA patients and less in TNBC tissues [64].…”

LXR-inverse agonism stimulates immune-mediated tumor destruction by enhancing CD8 T-cell activity in triple negative breast cancer

“…In particular pharmacological targeting of LXR-ligand production effectively overcome immunotherapy resistance in preclinical melanoma models 16,21 . LXR has also been cited as a marker for poor prognosis, particularly in African American TNBC patients 22,23 . In breast cancer overall, elevated lipid metabolism is irrevocably linked to poor clinical outcomes and treatment resistance 24–26 .…”