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Hypoxia-Driven TGFβ Modulation of Side Population Cells in Breast Cancer: The Potential Role of ERα

Lookup NU author(s): Dr Paraskevi Mallini, Dr Kamilla Mahkamova, Professor Thomas Lennard, Emeritus Professor John Kirby, Dr Gendie Lash, Dr Annette Meeson



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2023 by the authors. 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.

Publication metadata

Author(s): Mallini P, Chen M, Mahkamova K, Lennard TWJ, Pan Y, Wei D, Stemke-Hale K, Kirby JA, Lash GE, Meeson A

Publication type: Article

Publication status: Published

Journal: Cancers

Year: 2023

Volume: 15

Issue: 4

Online publication date: 09/02/2023

Acceptance date: 06/02/2023

Date deposited: 14/03/2023

ISSN (electronic): 2072-6694

Publisher: MDPI AG


DOI: 10.3390/cancers15041108


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