Signaling pathways governing breast cancer stem cells behavior

Breast cancer is the second common cancer and the leading cause of malignancy among females overall. Breast cancer stem cells (BCSCs) are a small population of breast cancer cells that play a critical role in the metastasis of breast cancer to other organs in the body. BCSCs have both self-renewal and differentiation capacities, which are thought to contribute to the aggressiveness of metastatic lesions. Therefore, targeting BCSCs can be a suitable approach for the treatment and metastasis of breast cancer. Growing evidence has indicated that the Wnt, NFκB, Notch, BMP2, STAT3, and hedgehog (Hh) signaling pathways govern epithelial-to-mesenchymal transition (EMT) activation, growth, and tumorigenesis of BCSCs in the primary regions. miRNAs as the central regulatory molecules also play critical roles in BCSC self-renewal, metastasis, and drug resistance. Hence, targeting these pathways might be a novel therapeutic approach for breast cancer diagnosis and therapy. This review discusses known signaling mechanisms involved in the stimulation or prevention of BCSC self-renewal, metastasis, and tumorigenesis.

Despite available interventions, these strategies may not always be the best treatment options for targeting BC metastasis [18]. Therefore, a better understanding of the molecular mechanisms involved in tumorigenesis of BC is required to develop more effective therapeutic strategies [19,20]. Breast cancer stem cells (BCSCs) are a small population of BC cells that play a critical role in the metastasis of BC to other organs in the body [21]. BCSCs have the ability to self-renew and to differentiate into specialized cells that are found in malignancy [22,23]. Accumulating evidence shows that BCSCs are the leading cause of tumor progression and resistance against conventional therapy [24][25][26]. Therefore, targeting BCSCs may be an appropriate approach for the treatment of BC [27][28][29][30]. This review discusses known signaling mechanisms involved in the stimulation or prevention of BCSC self-renewal, metastasis, and tumorigenesis.
There is a high degree of intertumor and intratumor heterogeneity in breast cancer [51,52]. Thus, a single tumor may contain BCSCs with distinct molecular profiles [53,54]. Based on immunohistochemical analyses, cells with the CD44+CD24−/low phenotype are not enough to characterize BCSC. Several candidate markers such as the ESA antigen, ALDH1 expression, Prominin-1 (CD133), and CD131 and the capacity to form spheroid can be independent factors for the characterization of BCSCs [49,55,56].

BMP2 signaling
In breast cancer xenograft models, BMP-2 can promote EMT transition and bone metastasis [89]. BMP2 via targeting CD44 expression and suppressing the Rb signaling pathway induces EMT, stemness, and chemoresistance in BCSCs [89]. Activation of the PI3K/ Akt pathway as well as Rb interaction with CD44 has been shown to play essential roles in BMP-2-dependent EMT in BCSCs [89]. However, BMPs are able to cause G1 arrest, increase apoptosis, and suppress BCSC proliferation [90]. Therefore, the BMP family may have dual behaviors in stimulation or suppression of BCSCs [91]. Thus, employing BMP family inhibitors may be useful for targeting BCSCs [49,92,93].

Notch signaling
The Notch pathway through JAG-1 and NOTCH-4 can stimulate and maintain the invasion, mesenchymal-like properties, and drug resistance of BCSCs [102,103]. NOTCH4 by targeting SLUG and GAS1 is involved in BC development [104]. In normal cells, the NUMB protein blocks the Notch intracellular domain (NICD) in the cytoplasm and inhibits the Notch pathway. miR-146a has been reported to suppress the function of NUMB, activate the Notch pathway, and trigger the formation of BCSCs [105]. Thus, downregulation of miR-146a and miR-146b expression may weaken the capacity for self-renewal in BCSCs [106]. MAP 17 (PDZKIP1) is a small cargo protein that negatively regulates the NUMB activity, activates the Notch pathway, and promotes the maintenance of BCSCs [107]. 6-Shogaol as a gingerderived compound by targeting the expression of the Notch-Hes1-Cyclin D1 (CYLD) axis can suppress autophagy and apoptosis and then blocks the growth of BCSCs [108]. MK-0752 is a gamma-secretase inhibitor that inhibits the NICD domain and targets the BCSC population (phases I and II) [109]. Vismodegib (GDC-0449) is a Notch/hedgehog inhibitor drug that inhibits BCSC growth in tamoxifen-resistant breast cancer (phase I) [110] (http://clinicaltrials.gov).

Suppression of tumorigenesis
Some miRNAs may act as tumor suppressors and overcome tumorigenesis and drug resistance in BSCS [138,152]. miR-34a is an important miRNA that targets the insulin-like growth factor II (IGFII), mRNA-binding protein (IMP3)-induced stemness, and Wnt/β-catenin signaling and decreases BCSC self-renewal [153]. miR-628 by targeting SOS Ras/Rac guanine nucleotide exchange factor 1 (SOS1) inhibits BCSC migration and invasion [154]. miR-140-5p as a critical tumor suppressor blocks the Wnt/β-catenin, SOX2, and SOX9 pathways and inhibits the growth, tumorsphere formation, and progression of BCSCs [155,156]. This miRNA through the Wnt1/ABCB1 pathway promotes the sensitivity of BCSCs to Dox [156]. miR-142-3p by targeting β-catenin pathway can reduce CD44, CD133, ALDH1, and radioresistance in BCSCs [157]. miR-4319 can suppress the expression of the E2F2 transcription factor and decrease the tumorigenicity of TNBCSC [158]. Another investigation shows that miR-130a-3p by targeting the expression of RAB5B (member of RAS oncogene family) inhibits the carcinogenic features of BCSCs [159,160]. miRNA Let-7 has been shown to block the Wnt pathway, inhibit the growth and stemness of BCSCs, and promote the anti-cancer effect of tamoxifen (a chemotherapeutic drug) [161]. Recent work has also identified Let-7c through estrogen-activated Wnt signaling can suppress the self-renewal abilities of BCSCs [162]. miR-205 via modulating STAT3 signaling reduces the expression of CD44 and ALDH1 stem-cell markers and inhibits BCSC migration and invasion [163]. miR-519d by targeting MCL-1 (a member of the proapoptotic Bcl-2 family) increases the sensitivity of BCSC to cisplatin (a chemotherapeutic drug) [164]. miR-600 through the Wnt pathway targets stearoyl desaturase 1 (SCD1) and reduces BCSC self-renewal and tumorigenicity [165]. Also, miRNA-1 has been identified that targets frizzled receptors (FZDs) in the Wnt pathway and decreases BCSC proliferation and metastasis [166]. miR-375 by degrading the HOXB3 gene reduces BCSC phenotypes, EMT, and tamoxifen resistance [167]. Therefore, tumorsuppressing miRNAs with their functional pathways could be introduced as an effective strategy for targeting BCSCs [168,169].

Conclusion
Several signal transduction pathways, including Wnt/βcatenin, hedgehog, Notch, BMPs, and PI3K/Akt/NFkB, are deregulated in BCSCs. These signaling pathways stimulate proliferation, migration, invasion, EMT, chemotherapy, and radiotherapy resistance in BCSCs. miRNAs also through several signaling pathways can regulate the stemness features and tumorigenesis of BCSCs. Inhibition of key signaling pathways with small molecule inhibitors, nanoparticles, herbal medicine, and genetic modifications might be effective therapeutic approaches for targeting BCSCs [31,85,170,171]. Authors' contributions Dr. Kai Song and Dr. Maryam Farzaneh have made contributions to the writing of the manuscript, the design of the figures, and the revision of the manuscript. All authors have approved the submitted version of the article and have agreed to be personally accountable for the author's own contributions and to ensure that questions related to the accuracy or integrity of any part of the work. All authors read and approved the final manuscript.

Funding
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Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding authors on reasonable request.

Declarations
Ethics approval and consent to participate Not applicable.