Abstract
Tumor cell heterogeneity poses a major hurdle in the treatment of cancer. Mammary cancer stem-like cells (MaCSCs), or tumor-initiating cells, are highly tumorigenic sub-populations that have the potential to self-renew and to differentiate. These cells are clinically important, as they display therapeutic resistance and may contribute to treatment failure and recurrence, but the signaling axes relevant to the tumorigenic phenotype are poorly defined. The zinc-finger transcription factor Kruppel-like factor 4 (KLF4) is a pluripotency mediator that is enriched in MaCSCs. KLF4 promotes RAS-extracellular signal-regulated kinase pathway activity and tumor cell survival in triple-negative breast cancer (TNBC) cells. In this study, we found that both KLF4 and a downstream effector, microRNA-206 (miR-206), are selectively enriched in the MaCSC fractions of cultured human TNBC cell lines, as well as in the aldehyde dehydrogenase-high MaCSC sub-population of cells derived from xenografted human mammary carcinomas. The suppression of endogenous KLF4 or miR-206 activities abrogated cell survival and in vivo tumor initiation, despite having only subtle effects on MaCSC abundance. Using a combinatorial approach that included in silico as well as loss- and gain-of-function in vitro assays, we identified miR-206-mediated repression of the pro-apoptotic molecules programmed cell death 4 (PDCD4) and connexin 43 (CX43/GJA1). Depletion of either of these two miR-206-regulated transcripts promoted resistance to anoikis, a prominent feature of CSCs, but did not consistently alter MaCSC abundance. Consistent with increased levels of miR-206 in MaCSCs, the expression of both PDCD4 and CX43 was suppressed in these cells relative to control cells. These results identify miR-206 as an effector of KLF4-mediated prosurvival signaling in MaCSCs through repression of PDCD4 and CX43. Consequently, our study suggests that a pluripotency factor exerts prosurvival signaling in MaCSCs, and that antagonism of KLF4-miR-206 signaling may selectively target the MaCSC niche in TNBC.
Highlights
Compelling experimental evidence supports the hierarchical organization of certain human tumor types, including breast cancer.[1,2,3,4,5,6] These tumors comprise heterogenous mixtures of tumor cell populations that include cancer stem-like cells (CSCs), typically defined by their ability to initiate tumors in limiting dilution assays
Kruppel-like factor 4 (KLF4) and miR-206 can promote Mammary cancer stem-like cells (MaCSCs) abundance miR-206 is highly expressed in basal-like breast cancers and
KLF4 and miR-206 in basal-like tumors derived from the C3(1)/SV40 large T antigen (C3(1)/TAg) genetically engineered mouse model (GEMM) (Figure 1c)
Summary
Compelling experimental evidence supports the hierarchical organization of certain human tumor types, including breast cancer.[1,2,3,4,5,6] These tumors comprise heterogenous mixtures of tumor cell populations that include cancer stem-like cells (CSCs), typically defined by their ability to initiate tumors in limiting dilution assays (that is, tumor-initiating cells, TICs). Functionally validated CSCs (termed MaCSCs (mammary CSCs)) have been identified by profiling the expression of cell surface markers such as PROCR (P) and ESA (E) and/or by assaying aldehyde dehydrogenase (ALDH) activity.[9,10,11,12] Despite this insight, the underlying mechanisms that mediate the MaCSC phenotype are unclear. For regulation of their abundance and/or their intrinsic properties such as resistance to cell death, several cellular signaling axes have been implicated including the WNT, NOTCH, TGFβ and SHH pathways.[13,14,15]
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