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Table 2 Preliminary mechanism of BCSC-related pathways associated with endocrine resistance

From: Utilizing the Hippo pathway as a therapeutic target for combating endocrine-resistant breast cancer

BCSC-related pathways

Association with BCSCs

Association with endocrine resistance

PI3K/Akt/mTOR

Heregulin-1β increases the cell fraction of CD44+/CD24 and activates both MAPK and PI3K/Akt/mTOR pathways [41]. CD44+CD24CD45 BCSCs isolated from primary ERα-positive breast carcinoma exhibit hyperactive genes involved in the PI3K pathway, including PIK3R1, PIK3R2, PIK3CA and EGFR [42]. CSC population plays a vital role during endocrine resistance by activation of the mTOR pathway [43]

Heregulin-1β also can regulate ER/HER family expression by upregulating HER family mRNA expression and downregulating ERα mRNA expression [41]. Deactivation of PI3K/Akt/mTOR signaling increases the sensitivity of breast cancer cells to tamoxifen [44]. The activation of the PI3K/Akt/mTOR signaling in response to endocrine therapy may indeed result in acquired endocrine resistance [45]

EGFR

ER + breast cancer cells become resistant to tamoxifen treatment through enhanced regulation of the loops of ER-α36-EGFR/HER2 [46]. Rapid ER signaling mediated by ER-α36 is involved in regulation of BCSCs [47]. And ER-α36 could also positively regulates the population of ALDH1 breast cancers and HER2 expression [48]. EGFR overexpression regulates the CD24lowCD44high and ALDH+ in BCSC phenotypes as well as clonal formation [49]

EGFR expression and HER-2 amplification exert lower levels of ER and less response to tamoxifen [50]. Loss of ER by activation of EGFR pathway induces tamoxifen resistance and aberrant EGFR expression which is relative to a poor prognosis in ER + breast carcinomas [51]

MAPK

Laminin reduces the expression of Nanog and Sox2, and inhibits the ability to form secondary mammospheres [52]. The effects of laminin are mediated by MAPK/ERK pathway [52]. The inhibitor of MAPK/ERK pathway reduces the size of mammospheres in MCF7 cells [53]. High expression of phosphorylated p38γ MAPK is associated with CSC population in breast cancer cell lines [54]

The influences of CXCR4 overexpression are related with SDF-1–mediated stimulation of downstream signaling through p38 MAPK and ERK1/2 [55]. Overexpression of CXCR4 improves the expression of ER-mediated gene and alters endocrine therapy sensitivity [55]. Overexpression of Krüppel-like factor 4 inhibits p38 and ERK signaling, and results in increased sensitivity to tamoxifen[56]. Heregulin-1β-stimulated pathways enable ERα-positive breast cancer cells to everolimus resistance via MAPK pathway [41]

Wnt

Wnt/β-catenin pathway is activated, and exhibits stem-like features with upregulated cancer stem cell markers Nanog and ALDH1 in endocrine-resistant breast cancer [57]

Molecules of Wnt pathway may be regarded as an intrinsic factor in the transition to tamoxifen resistance [58]. Endocrine-resistant cells have enrichment of stem-like properties including increase of BCSC-related genes, stimulation of Wnt/β-catenin pathway, and formation of mammospheres [57].Sensitivity in MCF7 stem cells to tamoxifen is increased by inactivation of Wnt/β-catenin pathway [59]

Hh

The activated Hh pathway regulates BCSCs by increasing GLI1 expression and enhancing the expression of Sox2 [60]

Treatment of tamoxifen-resistant xenografts with a Hh inhibitor suppresses tumor growth [61]. Hh pathways is regulated by PI3K pathway which has a protection of key components in Hh signaling from proteasomal degradation [61]. Hh signaling is activated by PI3K pathway in the endocrine-resistant breast tumor cells [62]. The levels of the Hh signaling component GLI1 are significantly improved in tamoxifen-resistant MCF-7 cells and T47D cells [61]

Notch

CD133hi BCSCs sustain self-renewal ability by an ER-independent manner, which exhibits the suppression of ER signaling caused by hormonal therapy and the upregulation of Notch3 [63].Short-term treatment with tamoxifen or fulvestrant inhibits cell proliferation but increases BCSC activity via activation of JAG1-NOTCH4 receptor both in xenograft tumors and patient-derived samples [18]

The reduction of Notch3 expression and activity abrogates hormonal therapy resistance and the expansion ability of CD133hi cancer cells [63]. The activation of Notch4 results in poor response of MCF7 to tamoxifen [64]. In xenograft tumors with tamoxifen resistance, Notch4 suppression inhibits BCSC activity [18]

TGF-β

TGF-β induces sphere-forming efficiency in MDA361 and BT474 cells by a dose-dependent manner [65]. However, TGF-β inhibits sphere-forming efficiency in MCF7 cells [65]. Treatment with TGF-β increases ALDH+ and CD24low/CD44+ CSC-enriched population in breast cancer cell lines [66]

The plasma levels of TGF-β are upregulated in the group of these patients with endocrine-resistant breast cancer, as compare with the healthy group [67]. High PI3K and Hh pathway activity is relative to shorter PFS of metastases during tamoxifen treatment, and high TGF-β and PI3K pathway activity with worse response in treatment [68]. The secretion about active TGF-β can be induced to more than eightfold with the treatment of anti-estrogen in MCF-7 cells, and the active TGF-β secreted by the MCF-7 cell line also could suppress the growth of an ER − breast cancer cell line [69]

  1. PFS progression-free survival