Endocrine-targeting therapies shift the breast microbiome to reduce estrogen receptor-α breast cancer risk.

Studies indicate that breast tissue has a distinct modifiable microbiome population. We demonstrate that endocrine-targeting therapies, such as tamoxifen, reshape the non-cancerous breast microbiome to influence tissue metabolism and reduce tumorigenesis. Using 16S sequencing, we found that tamoxifen alters β-diversity and increases Firmicutes abundance, including Lactobacillus spp., in mammary glands (MGs) of mice and non-human primates. Immunohistochemistry showed that lipoteichoic acid (LTA)-positive bacteria were elevated in tamoxifen-treated breast tissue. In B6.MMTV-PyMT mice, intra-nipple probiotic bacteria injections reduced tumorigenesis, altered metabolic gene expression, and decreased tumor proliferation. Probiotic-conditioned media selectively reduced viability in estrogen receptor-positive (ER+) breast cancer cells and altered mitochondrial metabolism in non-cancerous epithelial cells. Human tumor samples revealed that LTA-positive bacteria negatively correlated with Ki67, suggesting that endocrine therapies influence tumor-associated microbiota to regulate proliferation. Our data indicate that endocrine-targeting therapies modify the breast microbiome, corresponding with a shift in tissue metabolism to potentially reduce ER+ breast cancer risk.