Autophagy Differentially Regulates Distinct Breast Cancer Stem-like Cells in Murine Models via EGFR/Stat3 and Tgfβ/Smad Signaling

Abstract

Cancer stem-like cells contribute to tumor heterogeneity and have been implicated in disease relapse and drug resistance. Here we show the co-existence of distinct breast cancer stem-like cells (BCSC) as identified by ALDH+ and CD29hiCD61+ markers, respectively, in murine models of breast cancer. While both BCSC exhibit enhanced tumor initiating potential, CD29hiCD61+ BCSC displayed increased invasive abilities and higher expression of epithelial to mesenchymal (EMT) and mammary stem cell-associated genes, whereas ALDH+ BCSC were more closely associated with luminal progenitors. Attenuating the autophagy regulator FIP200 diminished the tumor-initiating properties of both ALDH+ and CD29hiCD61+ BCSC, as achieved by impairing either the Stat3 and TGFß/Smad pathways, respectively. Further, combining the Stat3 inhibitor Stattic and the Tgfß-R1 inhibitor LY-2157299 inhibited the formation of both epithelial and mesenchymal BCSC colonies. In vivo this combination treatment was sufficient to limit tumor growth and reduce BCSC number. Overall, our findings reveal a differential dependence of heterogeneous BCSC populations on divergent signaling pathways, with implications on how to tailor drug combinations to improve therapeutic efficacy.

Breast Cancer: Multiple Subtypes within a Tumor?

“…In breast cancers, although tumor cells are organized in a hierarchical manner where CSCs exhibit features of stem/progenitor cells [11], there is plasticity which allows the acquisition of CSC traits by bulk tumor cells [12]. Accordingly, it is conceivable that dynamic conversions as a result of differentiation and plasticity can give rise to tumors with cells that correspond to distinct differentiation states of the normal mammary gland hierarchy [13, 14]. Due to the plasticity of tumor cells, therapeutic strategies will need to consider all the cell types within the hierarchical structure of the tumor and not just CSCs alone, since re-emerging CSC populations can arise from bulk tumor cells [15, 16].…”

“…A continuum of differentiation states that are reflective of the normal mammary hierarchy (Figure 1) is plausible and would result in hierarchical heterogeneity within breast tumors [11, 14]. With regards to this, multiple independent studies have observed the presence of minimally overlapping distinct CSC populations within tumors based on the expression of established CSC markers such as CD44 hi /CD24 − , ALDH + , CD133 + or CD29 hi /CD61 + [13, 17–19]. The heterogeneity of the observed CSC populations could be a representation of the diversity in normal mammary stem/progenitor cells that are spatially and temporally regulated [20–31].…”

“…increased tumorigenic potential), this may be a generalization that need not necessarily hold true in every case. In fact, there are reports of more differentiated luminal breast cancer cells exhibiting equal tumor initiating capacity as basal/stem-like breast cancer cells [13, 19]. Further insights and elucidation of the normal mammary hierarchy, which are extensively covered by these reviews [20, 21, 32], will be vital to the understanding of various distinct CSC populations in breast tumors.…”

“…Additionally, comprehension of the intrinsic and niche factors that govern each of the normal mammary stem/progenitor cell states may shed light on the vulnerabilities of distinct CSC populations. This is especially important since there are indications that distinct CSCs may have differential susceptibilities to targeted therapies against CSC-associated pathways such as Notch, Stat3 and TGF-beta [13, 33]. …”

Silencing of Prrx2 Inhibits the Invasion and Metastasis of Breast Cancer both In Vitro and In Vivo by Reversing Epithelial-Mesenchymal Transition

“…Transcriptional factors such as Twist1, ZEB2, Snail and FOXC2 can directly or indirectly trigger the EMT [9]. However, the molecular mechanisms by which EMT and MET occur during cancer progression are still unclear [10]. …”