The Role of Serotonin in Breast Cancer Stem Cells

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.

Breast cancer and neurotransmitters: emerging insights on mechanisms and therapeutic directions

“…Kim et al reported that patients who received tramadol after breast cancer surgery had a decreased risk of postoperative recurrence and mortality, with the anti-tumor effect of tramadol appearing to involve inhibition of proliferation, induction of apoptosis, and effects on the serotonin 2B receptor and transient receptor potential vanilloid-1 expression [ 63 ]. More generally, antagonists of serotonin biosynthesis, transport, and activity appear to diminish breast cancer stem cell viability [ 64 ]. Serotonin production in a tumor sample may be a predictor of poor prognosis [ 65 ].…”

The therapeutic effect of traditional Chinese medicine on breast cancer through modulation of the Wnt/β-catenin signaling pathway

“…At the same time, some molecular markers, such as CD44 + /CD24 -/low ( Al-Hajj et al, 2003 ; Sheridan et al, 2006 ), ALDH1 + ( Ginestier et al, 2007 ; Morimoto et al, 2009 ), CD133 ( Kim et al, 2015 ), CD61 ( Vaillant et al, 2008 ), CD49f ( Ye et al, 2017 ), and CXCR4 ( Ablett et al, 2014 ; Trautmann et al, 2014 ), can be used as biomarkers to identify BCSCs, and may serve as therapeutic targets for small molecular inhibitors. Therefore, many researchers realize that targeting BCSCs is crucial to achieve long-lasting remission of breast cancer ( Gwynne et al, 2021 ). In experimental research, the common and unique characteristics of normal stem cells and cancer stem cells have been utilized to develop robust stem cell models.…”

Exploring neurotransmitters and their receptors for breast cancer prevention and treatment

“…Interestingly, TPH1 and 5-HTR 7 have been reported to be preferentially expressed in TNBC 114 . In addition, the serotonergic system has also been demonstrated to promote CSC-like activity in BC 116 .…”