Staphylococcus aureus-Derived Extracellular Vesicles Enhance the Efficacy of Endocrine Therapy in Breast Cancer Cells

Abstract

The microbiome involved in the human estrogen metabolism is known as the estrobolome. This study aimed to show that the estrobolome can be used in breast cancer treatment. We first analyzed the blood microbiome composition of healthy controls and patients with breast cancer. In particular, we investigated the bacteria producing β−glucuronidase and/or β−galactosidase, which are involved in estrogen metabolism in the human body. Staphylococcus species were more abundant in healthy controls than in breast cancer patients and therefore were selected for further analyses. The effect of Staphylococcus aureus on endocrine therapy was analyzed by a combination treatment with tamoxifen. Analysis of the microbiome of blood samples showed that species producing β−glucuronidase were more abundant in breast cancer patients than in healthy controls. Further experiments confirmed that the efficacy of tamoxifen increased when administered in conjugation with the extracellular vesicles (EVs) of S. aureus. Based on our results, we deduced that S. aureus EVs could potentially be used as adjuvants for breast cancer treatment in the future.

The Blood Microbiome and Health: Current Evidence, Controversies, and Challenges

“…Similarly, dysbiosis of the estrobolome in the blood of breast cancer patients has also been reported. β-glucuronidase-producing bacteria were predominant in breast cancer patients, whereas β-galactosidase-producing bacteria were more abundant in healthy individuals [ 36 ]. Interestingly, Staphylococcus, which was depleted in the breast cancer group, was identified as a key modulator of anti-estrogen (i.e., tamoxifen) efficacy [ 36 ].…”

“…β-glucuronidase-producing bacteria were predominant in breast cancer patients, whereas β-galactosidase-producing bacteria were more abundant in healthy individuals [ 36 ]. Interestingly, Staphylococcus, which was depleted in the breast cancer group, was identified as a key modulator of anti-estrogen (i.e., tamoxifen) efficacy [ 36 ]. When estrogen-receptor positive breast tumor cells were cotreated with tamoxifen and S. aureus -derived extracellular vesicles, the AKT and ERK oncogenic signaling pathways were greatly suppressed, leading to more cell death [ 36 ].…”

Analysis of the Impact of the Presence of Phylum Cyanobacteria in the Microbiome of Patients with Breast Cancer on Their Prognosis

“…Serum samples were collected from the participants using the same method as that used in the previous studies [20,21]. Blood samples were collected into serum vacuum separator tubes.…”

“…For this, the MiSeq system and application (Illumina, San Diego, CA, USA) suitable for the NGS of bacteria were used. The primers used and the corresponding sequences are the following: 16S_V3_F (5 -TCGTCGGCAGCGTCAGATGTGTATAAGA GACAGCCTACGGGNGGCWGCAG-3 ) and 16S_V4_R (5 -GTCTCGTGGGCTCGGAGAT GTATAAGAGAGACAGGAC-TACHVGGGTATCTAATCC-3 ), which are the same as those used in the previous studies [20,21]. Libraries were prepared, and each amplicon was sequenced according to the manufacturer's guidelines.…”

“…Bacterial extracellular vesicles contain nucleic acids and metabolites and are present in all body fluids, especially in the blood [19]. Previous studies have shown that there is a relationship between the composition of the microbiome in extracellular vesicles of body fluids and breast cancer [20,21]. In this study, the effect of a phylum Cyanobacteriacontaining microbiome on the prognosis of patients with breast cancer was investigated.…”