Comparative Gene Signature of (−)-Oleocanthal Formulation Treatments in Heterogeneous Triple Negative Breast Tumor Models: Oncological Therapeutic Target Insights

Abstract

Triple negative breast cancer (TNBC) heterogeneity and limited therapeutic options confer its phenotypic aggressiveness. The discovery of anti-TNBC natural products with valid molecular target(s) and defined pharmacodynamic profile would facilitate their therapeutic nutraceutical use by TNBC patients. The extra-virgin olive oil (EVOO) is a key Mediterranean diet ingredient. S-(−)-Oleocanthal (OC) leads the bioactive anti-tumor EVOO phenolic ingredients. A previous study reported the solid dispersion formulated OC with (+)-xylitol (OC-X) suppressed the in vivo progression and recurrence of the TNBC MDA-MB-231 cells. This study investigates the ability of OC-X formulation to suppress the in vivo heterogeneous BC initiation and progression utilizing advanced preclinical transgenic MMTV-PyVT and TNBC PDX mouse models. Furthermore, the clustering of the gene expression profiles in MMTV-PyVT and PDX mouse tumors treated with OC-X acquired by a Clariom S microarray analysis identified the distinctly affected genes. Several affected novel signature genes identified in response to OC-X treatments and proved overlapped in both mouse and human tumor models, shedding some lights toward understanding the OC anticancer molecular mechanism and assisting in predicting prospective clinical outcomes. This study provides molecular and preclinical evidences of OC-X potential as a nutraceutical suppressing heterogeneous TNBC model and offers preliminary gene-level therapeutic mechanistic insights.

The Sda Carbohydrate Antigen and Its Biosynthetic Enzyme B4GALNT2 in Health and Disease.

“…Importantly, this model showed that the phenotypic effects were oriented toward reduced malignancy independently on sLe x inhibition [67]. Consistent with TCGA data, experimental studies with triple negative breast cancer cell lines have shown a positive correlation between high B4GALNT2 and malignancy [68,69]. In particular, it has been shown that the B4GALNT2 protein is able to interact with proteins of the major histocompatibility complex (HLA-B) [69].…”

Influence of Olive Oil and Its Components on Breast Cancer: Molecular Mechanisms

“…In vivo, intragastric administration with oleocanthal (7.5 mg/kg daily for seven weeks) suppressed the initiation and incidence of mammary carcinogenesis in MMTV-PyVT mice developing spontaneous mammary tumors and in a breast cancer patient-derived xenograft model, concomitantly with transcriptomic changes in tumors and with the downregulation of Myc being a key event [155]. In an orthotopic nude mouse model using the MDA-MB-231/GFP human breast cancer cell line, 5 mg/kg (-)-oleocanthal reduced tumor growth and inhibited tumor activation of c-Met, the proliferation marker Ki-67 and the expression of vessel formation marker CD31 [156].…”

The Cancer-Associated Antigens Sialyl Lewisa/x and Sda: Two Opposite Faces of Terminal Glycosylation

“…Little is known about B4GALNT2 in BRCA. A recent study reported a systemic upregulation of B4GALNT2 in an experimental model of breast cancer [ 45 ]. Consistently, TCGA data analysis showed that in normal breast tissues as well as in the majority of BRCA tissues, the level of B4GALNT2 mRNA expression was nearly undetectable ( Figure 5 C,D), although a minority of the cancer cases displayed a level of activity similar with that of colon.…”