Abstract
Breast tumors were the first tumors of epithelial origin shown to follow the cancer stem cell model. The model proposes that cancer stem cells are uniquely endowed with tumorigenic capacity and that their aberrant differentiation yields non-tumorigenic progeny, which constitute the bulk of the tumor cell population. Breast cancer stem cells resist therapies and seed metastases; thus, they account for breast cancer recurrence. Hence, targeting these cells is essential to achieve durable breast cancer remissions. We identified compounds including selective antagonists of multiple serotonergic system pathway components required for serotonin biosynthesis, transport, activity via multiple 5-HT receptors (5-HTRs), and catabolism that reduce the viability of breast cancer stem cells of both mouse and human origin using multiple orthologous assays. The molecular targets of the selective antagonists are expressed in breast tumors and breast cancer cell lines, which also produce serotonin, implying that it plays a required functional role in these cells. The selective antagonists act synergistically with chemotherapy to shrink mouse mammary tumors and human breast tumor xenografts primarily by inducing programmed tumor cell death. We hypothesize those serotonergic proteins of diverse activity function by common signaling pathways to maintain cancer stem cell viability. Here, we summarize our recent findings and the relevant literature regarding the role of serotonin in breast cancer.
Highlights
Breast cancer is the second most common cancer in women and the leading cause of cancer-related deaths worldwide [1]
These observations suggest that 5-HT receptors (5-HTRs) or their downstream effectors can function as oncogenes to stimulate signaling pathways active in breast tumors and that their selective antagonists may enhance the sensitivity of 5-HT producing breast tumors to kinase inhibitors
In silico mining of gene expression profiles of breast tumor cell lines that overexpressed individual components of receptor tyrosine kinase (RTK) signaling pathways revealed that epidermal growth factor, a component of the chemically defined media required for sphere formation, increased the abundance of MAOA transcripts [57]
Summary
Breast cancer is the second most common cancer in women and the leading cause of cancer-related deaths worldwide [1]. Despite increased screening and new targeted therapies, the global incidence of breast cancer continues to increase [2]. Cytotoxic therapies used to treat breast cancer frequently do not achieve long lasting remissions. Roughly 30% of women diagnosed with invasive breast cancer relapse and 90% of these individuals die from metastases. New therapies are needed that ensure long lasting remissions
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