ProMetTre scientists have made a breakthrough discovery in cancer research by identifying a novel protein in breast cancer that is affected by cell stress and is not present in normal breast cells.
Our research shows a link between molecular stress, how a cancer can spread (metastasise) and the development of drug resistance. We are working to translate our findings to improve the prognosis for cancer patients.
Discovery of a new protein in breast cancer that is influenced by growth signalling and cell stress
The EGR4 protein plays an important role in the proliferation of small cell lung cancer.
Our research identified a new, shortened version of this protein found in breast cancer cells, we named it EGR4-S
1. Treating breast cancer cells with drugs that block growth signalling reduced EGR4-S expression
2. However, sustained, high-dose treatment led to less repression of EGR4-S
3. We also identified an inverse relationship between cell stress and EGR4-S
Cell stress suppresses
growth rate BUT enhanced properties associated with metastatic potential
RESEARCH ON STRESS IN CANCER
Chronic stress has been demonstrated in mouse models to promote cancer metastasis [1, 2]. More acutely, stress hormones that circulate in the body, such as adrenaline and noradrenaline, directly promote malignant features of cancer in vitro [3-10]. Additionally, we know cortisol and other glucocorticoids promote tumour growth [11, 12] and that breast cancer patients with higher tumour expression of glucocorticoid receptors have a worse prognosis than those with lower glucocorticoid receptor expression [13, 14].
At the cellular level, stress also has an association with advanced disease, drug resistance and metastasis in many types of cancer [15-17]. One response to cellular stress, called the heat shock response, is triggered by many forms of stress including heat, chemicals and infections, where the response acts to maintain intracellular protein homeostasis and protect the cell against stress-induced death .
As part of the heat shock response to cell stress, there is an accumulation of heat shock proteins (HSPs) within the cell [19, 20]. Increased expression of HSPs is frequently observed in several types of solid tumours  with stressful features in the tumour microenvironment (such as low oxygen, low glucose and acidosis) leading to this HSP induction [22, 23]. As a cancer progresses, the expression of HSPs appears to increase concurrently and, consistent with this, many high grade tumours have highly elevated HSP expression. Specifically, high levels of HSPs have all been shown to support various tumourigenic properties including enhanced cancer cell invasion, metastasis and capacity for survival, and their increased expression frequently correlates with poor patient response to therapy and worse patient prognosis in terms of overall survival [24, 25]. Recent evidence from 500 patients with metastatic solid tumours revealed a global increase in stress response compared to normal tissues .
The ‘master regulator’ of the heat shock response is the transcription factor Heat Shock Factor 1 (HSF1) which is activated when a cell is under stress [20, 27]. HSF1 has long been reported to play crucial roles in cancer progression, metastasis and drug resistance [27, 28]. This cell stress response is part of the focus of our research.
SUGGESTED further reading:
Eckerling et al. (2021) – https://doi.org/10.1038/s41568-021-00395-5
Falcinelli et al. (2021) – https://doi.org/10.1158/0008-5472.CAN-21-0684
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- Du, P., et al., Chronic stress promotes EMT-mediated metastasis through activation of STAT3 signaling pathway by miR-337-3p in breast cancer. Cell Death Dis, 2020. 11(9): p. 761 DOI: 10.1038/s41419-020-02981-1.
- Liu, J., et al., A novel beta2-AR/YB-1/beta-catenin axis mediates chronic stress-associated metastasis in hepatocellular carcinoma. Oncogenesis, 2020. 9(9): p. 84 DOI: 10.1038/s41389-020-00268-w.
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