Abstract
Triple-negative breast cancer (TNBC) is a highly aggressive cancer for which targeted therapeutic agents are limited. Growing evidence suggests that TNBC originates from breast cancer stem cells (BCSCs), and elucidation of the molecular mechanisms controlling BCSC proliferation will be crucial for new drug development. We have previously reported that the lysosphingolipid sphingosine-1-phosphate mediates the CSC phenotype, which can be identified as the ALDH-positive cell population in several types of human cancer cell lines. In this study, we have investigated additional lipid receptors upregulated in BCSCs. We found that lysophosphatidic acid (LPA) receptor 3 was highly expressed in ALDH-positive TNBC cells. The LPAR3 antagonist inhibited the increase in ALDH-positive cells after LPA treatment. Mechanistically, the LPA-induced increase in ALDH-positive cells was dependent on intracellular calcium ion (Ca2+), and the increase in Ca2+ was suppressed by a selective inhibitor of transient receptor potential cation channel subfamily C member 3 (TRPC3). Moreover, IL-8 production was involved in the LPA response via the activation of the Ca2+-dependent transcriptional factor nuclear factor of activated T cells. Taken together, our findings provide new insights into the lipid-mediated regulation of BCSCs via the LPA-TRPC3 signaling axis and suggest several potential therapeutic targets for TNBC.
Highlights
Breast cancer is the major cause of cancer death among women worldwide [1]
We have previously reported that the lysosphingolipid sphingosine-1-phosphate mediates the cancer stem cells (CSCs) phenotype, which can be identified as the aldehyde dehydrogenase (ALDH)-positive cell population in several types of human cancer cell lines [23]
Since the expression level of LPAR3 in ALDH-positive cells was 13.2-fold higher than that of LPAR6 in ALDH-positive cells (Figure S1), we focused on LPAR3 in breast cancer stem cells (BCSCs)
Summary
Breast cancer is the major cause of cancer death among women worldwide [1]. Triplenegative breast cancer (TNBC), which represents approximately 15% of all breast cancers, is characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and erb-b2 receptor tyrosine kinase 2 (ERBB2/HER2) expression [2]. The early detection and elucidation of the molecular mechanisms underlying breast cancer malignancy have progressed, cellular heterogeneity is considered to result in therapeutic resistance and promote cancer malignancy in many types of cancer, including breast cancer [3]. Growing evidence suggests that cancer stem cells (CSCs; called tumorinitiating cells), a minor population of cancer cells with stem cell properties, are major drivers of cancer heterogeneity [4–6] This minor population produces the bulk of cancer cells through continuous self-renewal and differentiation. We found that TRPC3, a calcium channel, is essential for LPA-induced proliferation of BCSCs via NFAT-mediated IL-8 secretion. These results implicate components of the LPA signaling pathway as therapeutic targets in TNBC
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