2012
DOI: 10.1007/s13277-012-0383-6
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Antitumor effect of the mTOR inhibitor everolimus in combination with trastuzumab on human breast cancer stem cells in vitro and in vivo

Abstract: This study evaluated the effects of a mammalian target of mTOR inhibitor everolimus alone or in combination with trastuzumab on stem cells from HER2-overexpressing primary breast cancer cells and the BT474 breast cancer cell line in vitro and in vivo. For the in vitro studies, we sorted ESA(+)CD44(+)CD24(-/low) cells as stem cells from primary breast cancer cells and BT474 cells using flow cytometry. The MTT assay was used to quantify the inhibitory effect of the drugs on total cells and stem cells specificall… Show more

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Cited by 50 publications
(35 citation statements)
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“…FAK is activated by HER2 (Nahta 2012) and can integrate signalling downstream of HER2 and other receptors resulting in the activation of the PI3K/Akt pathway (Nahta 2012). Both HER2 crosstalk and augmented PI3K/Akt signalling have been implicated in HER2 therapy resistance (Nahta 2012, Zhu et al 2012, and FAK, through its involvement with HER2, is emerging as an important player in trastuzumab resistance , Yang et al 2010. In this study, we set out to investigate the therapeutic potential of FAK in the context of ERC/HER2C breast cancer.…”
Section: Discussionmentioning
confidence: 99%
“…FAK is activated by HER2 (Nahta 2012) and can integrate signalling downstream of HER2 and other receptors resulting in the activation of the PI3K/Akt pathway (Nahta 2012). Both HER2 crosstalk and augmented PI3K/Akt signalling have been implicated in HER2 therapy resistance (Nahta 2012, Zhu et al 2012, and FAK, through its involvement with HER2, is emerging as an important player in trastuzumab resistance , Yang et al 2010. In this study, we set out to investigate the therapeutic potential of FAK in the context of ERC/HER2C breast cancer.…”
Section: Discussionmentioning
confidence: 99%
“…In liver cancer stem cell (LCSC) lines, simultaneous treatment of sorafenib with PKI-587 resulted in a 47% and 19% increase in inhibition of LCSC cell proliferation compared with sorafenib or PKI-587 lone treatment respectively (Gedaly et al, 2013). For breast cancer, concurrent use of everolimus with trastuzumab resulted in greater reduction in the in vitro tumorigenicity as well as in vivo growth of patient derived and BT474 CSCs than either agent alone (Zhu et al, 2012). Addition of rapamycin, everolimus, or PF-04691502 to tamoxifen therapy also reduced mammosphere formation of patient derived CSCs through ameliorating tamoxifen induced mTOR activation in these CSCs (Karthik et al, 2015).…”
Section: Mtor Inhibitors For Modulating Mtor Activity To Combat Cancementioning
confidence: 99%
“…Therefore, to be effective, anti-HER2 breast carcinoma approaches will need to combine agents that are selectively toxic to HER2-positive CSCs (i.e., the trastuzumab antibody itself) by targeting the bulk, non-CSC populations within HER2-positive breast carcinomas (e.g., taxane-or anthracycline-based chemotherapy), as well as by inhibiting EMT-related transitions from non-CSC to CSC states and/or from a trastuzumab-responsive CSC (epithelial) state to a non-responsive (mesenchymal) state (e.g., salinomycin, mTOR inhibitors, CD44-targeting antibodies, polyamine metabolism inhibitors and AMPK agonists such as metformin). 89,103,[145][146][147][148][149][150][151][152][153][154][155] CSCs "are made, not born": Incorporating "mesenchymal transition signatures" to predict the anti-CSC efficacy of trastuzumab. Assuming that CSCs "are made, not born," and that CSCs are flexible entities that can transform their trastuzumab-sensitivity-state, we must determine how to integrate CSCand/or EMT-related biomarkers with currently available clinic-pathological is mostly related to its ability to specifically and efficiently target HER2-driven populations of CSCs and that, somewhat counterintuitively, a variety of recently discovered mechanisms of escape from trastuzumab appear to involve many of the same well-accepted biomarkers implicated in the biology of CS-like, tumor-initiating cells.…”
Section: Molecular Forecasting Of Her2-positive Breast Carcinomas Basmentioning
confidence: 99%