A critical unmet medical need is to understand why some patients diagnosed with hormone receptor (HR+,
estrogen- and progesterone-receptor positive; Her2 negative) breast cancer experience recurrences with distant
metastatic disease whereas others do not, despite similar treatment. This is a significant issue considering that
the majority of patients diagnosed with breast cancer and that experience metastatic relapse have HR+ tumors.
Metastatic spread occurs early, often prior to the detection of the primary mass, and is facilitated by crosstalk
between the tissue and developing tumor. This gives rise to the possibility that differences in the normal tissue
environment exist which enhance the risk for metastatic disease. However, the mechanisms through which
changes arise in the mammary tissue environment and their contributions to metastatic breast cancer remain
largely undefined. We recently established gut commensal dysbiosis, defined as an inflammatory microbiome
with low biodiversity, enhances metastasis of HR+ tumors. Establishing dysbiosis prior to tumor initiation
significantly enhanced dissemination of tumor cells into the blood, distal lymph nodes, and lungs, with no impact
upon primary tumor growth. Dysbiosis enhanced the accumulation of mast cells into the normal mammary tissue
of non-tumor-bearing mice, whereas inhibition of mast cell degranulation significantly reduced metastatic
dissemination. These results indicated an important role for tissue-associated mast cells in the promotion of
breast tumor dissemination. Mechanistically, we demonstrate that blockade of CCL2 prior to tumor initiation is
sufficient to reduce mast cell accumulation in the mammary tissue and to diminish dysbiosis-induced
dissemination of HR+ tumor cells. The goal of this proposal is to define how gut commensal dysbiosis distally
orchestrates cellular and molecular changes in normal mammary tissues of non-tumor-bearing mice that
enhance susceptibility to HR+ tumor dissemination. Aim 1 will define how commensal dysbiosis distally changes
the normal (non-tumor-bearing) mammary tissue immune environment to favor early HR+ tumor dissemination.
We will integrate a variety of approaches to investigate the link between the gut microbiome, host metabolism,
and metastatic breast cancer. Aim 2 will establish how mast cells promote early dissemination of HR+ tumors.
The goal of this aim will be to define how mast cells are activated in mammary tissues of mice with dysbiosis
and establish how mast cells initiate metastasis of HR+ tumors through interactions with tissue fibroblasts and
macrophages. These mechanistic studies will have the potential to unveil novel therapeutic targets for the
prevention of metastatic breast cancer, targets that could be identifiable prior to a tumor diagnosis. Considering
the role of the gut commensal dysbiosis, modification of microbiome or targeting of commensal-associated
metabolites emerges as a potential low cost therapeutic to prevent or reduce the incidence of metastatic breast
cancer.
