A Procarcinogenic Colon Microbe Promotes Breast Tumorigenesis and Metastatic Progression and Concomitantly Activates Notch and β-Catenin Axes

Abstract

The existence of distinct breast microbiota has been recently established, but their biological impact in breast cancer remains elusive. Focusing on the shift in microbial community composition in diseased breast compared with normal breast, we identified the presence of Bacteroides fragilis in cancerous breast. Mammary gland as well as gut colonization with enterotoxigenic Bacteroides fragilis (ETBF), which secretes B. fragilis toxin (BFT), rapidly induces epithelial hyperplasia in the mammary gland. Breast cancer cells exposed to BFT exhibit “BFT memory” from the initial exposure. Intriguingly, gut or breast duct colonization with ETBF strongly induces growth and metastatic progression of tumor cells implanted in mammary ducts, in contrast to nontoxigenic Bacteroides fragilis. This work sheds light on the oncogenic impact of a procarcinogenic colon bacterium ETBF on breast cancer progression, implicates the β-catenin and Notch1 axis as its functional mediators, and proposes the concept of “BFT memory” that can have far-reaching biological implications after initial exposure to ETBF. Significance: B. fragilis is an inhabitant of breast tissue, and gut or mammary duct colonization with ETBF triggers epithelial hyperplasia and augments breast cancer growth and metastasis. Short-term exposure to BFT elicits a “BFT memory” with long-term implications, functionally mediated by the β-catenin and Notch1 pathways. This article is highlighted in the In This Issue feature, p. 995

Comprehensive profiles and diagnostic value of menopausal-specific gut microbiota in premenopausal breast cancer

“…Two populations, control and breast cancer populations, were divided according to the same age parameters. Correlation analysis provided critical evidence of two species of Bacteroides fragilis in young women with premenopausal breast cancer, which provides the first clinical evidence and is supported by the findings of Parida et al 34 . Another species of Klebsiella pneumoniae in postmenopausal women with older breast cancer requires further investigation.…”

“…In addition , Bacteroides fragilis is an oncobiome that contributes to colorectal cancer formation by inducing inflammation and DNA damage 33 . In breast cancer, a critical study demonstrated that Bacteroides fragilis exists in breast tissues and colonizes the gut to promote breast tumorigenesis and metastatic progression through the axes of the Notch and β-catenin pathways 34 . In postmenopausal breast cancer patients, Akkermansia muciniphila functions as a probiotic in individuals with obesity and diabetes.…”

“…In the pathway of androstenedione degradation, which is converted to estrogen via the aromatase enzyme in the ovaries of premenopausal women. In addition to steroid-related pathways, the oncogenic-related pathway may be partially related to the activation of the Notch and β-catenin pathways of Bacteroides fragilis 34 . The microbiome of postmenopausal breast cancer patients is involved in chemical carcinogenesis and aldosterone-related pathways.…”

Bacterial extracellular vesicles as bioactive nanocarriers for drug delivery: Advances and perspectives

“…The close relationship of gut microbiota and cancer in organs has become fully appreciated in recent decades [ 110 ]. To date, microbiome dysbiosis has been identified in colorectal cancer [ 111 , 112 ], breast cancer [ 113 ], lung cancer [ 114 ], liver cancer [ 115 ], and melanoma [ 116 ]. In addition, bacteria inside colorectal cancer travel along with tumor cells during liver metastasis, and metronidazole treatment reduces the Fusobacterium load and overall tumor growth [ 117 ].…”

Crosstalk between autophagy and microbiota in cancer progression

“… [ 68 ] Breast Cancer Enterotoxigenic Bacteroides fragilis (ETBF) Tumor promotion Proliferation and migration ETBF triggers breast cancer growth and metastasis through β-catenin and Notch1 pathways. [ 69 ] Faecalibacterium prausnitzii Tumor suppression Proliferation F. prausnitzii suppresses the growth of breast cancer cells through inhibition of IL-6/STAT3 pathway. [ 70 ] FadA Fusobacterium adhesin A, STAT3 Signal transducer and activator of transcription3, TLR2 toll-like receptor2, TLR4 toll-like receptor4, ROS reactive oxygen species, PCWBR2 putative cell wall binding repeat 2, SGMB Streptococcus gallolyticus member bacteria, IL-1 interleukin 1, COX-2 cyclooxygenase-2, IL-8 interleukin 8, CCR5 CC chemokine receptor 5, VCAM1 Vascular cell adhesion molecular 1, CAF cancer-associated fibroblasts, ESCC esophageal squamous cell carcinoma, IL-1β interleukin 1β, IL-23 interleukin 23, PI3K phosphatidylinositol-3 kinase, HCC hepatocellular carcinoma, PDCD4 programmed cell death 4, AP-1 activating protein-1 …”