Defining the role of PTEN in triple negative breast cancer (TNBC): an experimental and computational approach

Abstract

Breast cancer stands as a complex and heterogeneous disease that poses an escalating global public health concern. Among its diverse subtypes, triple-negative breast cancer (TNBC) is particularly notorious for its aggressive nature and inferior prognosis compared to other subtypes. Researchers grapple with the significant challenge of developing effective therapies for this malignancy. A contributing factor is the prominent lack of viable treatment options for this form of cancer. A pivotal element in this context is the tumour suppressor phosphatase and tensin homolog (PTEN), which is frequently found to be inactivated in TNBC.
This study is driven by two principal objectives. Firstly, it aims to elucidate the mechanisms by which PTEN becomes downregulated or inactivated in cell lines of breast cancer. Secondly, the study seeks to comprehensively gauge the response of TNBC cell lines upon the reintroduction of PTEN.
The study employs a two-fold methodology, integrating both in silico and wet lab analyses.
The in-silico analyses revealed a significant negative correlation between PTEN expression and the Buffa hypoxia signature within TNBC datasets, as identified through Gene Set Variation Analysis (GSVA) using hallmark pathways. This strong association suggests that hypoxia is tightly linked to PTEN downregulation at the level of transcription in clinical TNBC samples, providing insights into the influence of tumour microenvironment of PTEN loss.
Building upon these findings, wet lab results corroborate the hypothesis that hypoxia exerts a direct influence on PTEN in TNBC cell lines. This pertains to both transcriptional and protein levels, as evidenced by the effects observed in TNBC cell lines treated with DMOG, a hypoxia mimic drug. Encouragingly, the HIF inhibitor employed in this investigation demonstrated its efficacy in restoring PTEN expression in TNBC cells treated with DMOG.
Notably, TNBC frequently manifests reduced levels of PTEN, accompanied by heightened AKT activation. This marked dependence on the oncogenic pathway becomes a hallmark of these tumours, crucial for their survival and advancement. The phenomenon of cancer cells becoming "addicted" to oncogenic signalling lies at the core of drug resistance, enabling these cells to evade therapeutic interventions. Furthermore, scrutiny of the RNA-Seq dataset associated with the PTEN-induced cell line unveiled a cascade of pathways, notably the PI3K_AKT_mTOR pathway. This pathway exhibited initial suppression within a short time frame, followed by reactivation after prolonged treatment. Thus, this pathway could potentially bear clinical implications tied to the failure of drug treatments. Intriguingly, our last analysis suggests that a protein called Protein Tyrosine Kinase 2 Beta (PTK2B) bypasses the inhibitory impact imposed by PTEN, inducing abnormal growth and proliferation via activated AKT. Grasping the mechanisms by which PTK2B exerts its influence on the PI3K/AKT/mTOR signalling pathway may provide deeper insight into the resistance of breast cancer cells to treatments and to the natural mechanisms aimed at repressing tumours for this subtype. To comprehensively unravel the intricacies surrounding the reintroduction of PTEN into cells, this study underscores the need for further in-depth analysis.
In conclusion, this study provides novel insight into the mechanism of PTEN inactivation in TNBC, highlighting hypoxia as a key transcription repressor. It confirms that HIF-1α inhibition restores PTEN expression and demonstrates that reintroduction PTEN initially suppresses oncogenic pathways before triggering compensatory reactivation via PTK2B. These findings establish a potential feedback loop of resistance and underscore PTK2B as a promising therapeutic target to enhance PTEN-based strategies in TNBC.

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ORCID for Yihua Wang: orcid.org/0000-0001-5561-0648

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