TY - JOUR
T1 - Hypoxia-Driven TGFβ Modulation of Side Population Cells in Breast Cancer
T2 - The Potential Role of ERα
AU - Mallini, Paraskevi
AU - Chen, Miaojuan
AU - Mahkamova, Kamilla
AU - Lennard, Thomas W.J.
AU - Pan, Yue
AU - Wei, Dan
AU - Stemke-Hale, Katherine
AU - Kirby, John A.
AU - Lash, Gendie E.
AU - Meeson, Annette
N1 - Funding Information:
The STR DNA fingerprinting was done by the Cancer Centre Support Grant-funded Characterized Cell Line core, NCI # CA016672. This work was supported by staff of the Newcastle University Flow Cytometry Core facility, the Newcastle University Single Cell Genomics facility and the Newcastle University Bioinformatics facility. In addition, the single cell work was supported by an MRC-Newcastle University Single Cell Unit infrastructure award.
Publisher Copyright:
© 2023 by the authors.
PY - 2023/2
Y1 - 2023/2
N2 - Epithelial-to-mesenchymal transition (EMT) is known to be important in regulating the behaviour of cancer cells enabling them to acquire stem cell characteristics or by enhancing the stem cell characteristics of cancer stem cells, resulting in these cells becoming more migratory and invasive. EMT can be driven by a number of mechanisms, including the TGF-β1 signalling pathway and/or by hypoxia. However, these drivers of EMT differ in their actions in regulating side population (SP) cell behaviour, even within SPs isolated from the same tissue. In this study we examined CoCl2 exposure and TGF-β driven EMT on SP cells of the MDA-MB-231 and MCF7 breast cancer cell lines. Both TGF-β1 and CoCl2 treatment led to the depletion of MDA-MB-231 SP. Whilst TGF-β1 treatment significantly reduced the MCF7 SP cells, CoCl2 exposure led to a significant increase. Single cell analysis revealed that CoCl2 exposure of MCF7 SP leads to increased expression of ABCG2 and HES1, both associated with multi-drug resistance. We also examined the mammosphere forming efficiency in response to CoCl2 exposure in these cell lines, and saw the same effect as seen with the SP cells. We suggest that these contrasting effects are due to ERα expression and the inversely correlated expression of TGFB-RII, which is almost absent in the MCF7 cells. Understanding the EMT-mediated mechanisms of the regulation of SP cells could enable the identification of new therapeutic targets in breast cancer.
AB - Epithelial-to-mesenchymal transition (EMT) is known to be important in regulating the behaviour of cancer cells enabling them to acquire stem cell characteristics or by enhancing the stem cell characteristics of cancer stem cells, resulting in these cells becoming more migratory and invasive. EMT can be driven by a number of mechanisms, including the TGF-β1 signalling pathway and/or by hypoxia. However, these drivers of EMT differ in their actions in regulating side population (SP) cell behaviour, even within SPs isolated from the same tissue. In this study we examined CoCl2 exposure and TGF-β driven EMT on SP cells of the MDA-MB-231 and MCF7 breast cancer cell lines. Both TGF-β1 and CoCl2 treatment led to the depletion of MDA-MB-231 SP. Whilst TGF-β1 treatment significantly reduced the MCF7 SP cells, CoCl2 exposure led to a significant increase. Single cell analysis revealed that CoCl2 exposure of MCF7 SP leads to increased expression of ABCG2 and HES1, both associated with multi-drug resistance. We also examined the mammosphere forming efficiency in response to CoCl2 exposure in these cell lines, and saw the same effect as seen with the SP cells. We suggest that these contrasting effects are due to ERα expression and the inversely correlated expression of TGFB-RII, which is almost absent in the MCF7 cells. Understanding the EMT-mediated mechanisms of the regulation of SP cells could enable the identification of new therapeutic targets in breast cancer.
KW - 4-hydroxytamoxifen
KW - breast cancer stem cells
KW - CoCl
KW - cytokines
KW - hypoxia
KW - side population cells
KW - TGFβ
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U2 - 10.3390/cancers15041108
DO - 10.3390/cancers15041108
M3 - Article
C2 - 36831452
AN - SCOPUS:85149113834
SN - 2072-6694
VL - 15
JO - Cancers
JF - Cancers
IS - 4
M1 - 1108
ER -