Targeting the intrinsically disordered architectural High Mobility Group A (HMGA) oncoproteins in breast cancer: learning from the past to design future strategies

ABSTRACT

Introduction

Triple-negative breast cancer (TNBC) is the most difficult breast cancer subtype to treat because of its heterogeneity and lack of specific therapeutic targets. High Mobility Group A (HMGA) proteins are chromatin architectural factors that have multiple oncogenic functions in breast cancer, and they represent promising molecular therapeutic targets for this disease.

Areas covered

We offer an overview of the strategies that have been exploited to counteract HMGA oncoprotein activities at the transcriptional and post-transcriptional levels. We also present the possibility of targeting cancer-associated factors that lie downstream of HMGA proteins and discuss the contribution of HMGA proteins to chemoresistance.

Expert opinion

Different strategies have been exploited to counteract HMGA protein activities; these involve interfering with their nucleic acid binding properties and the blocking of HMGA expression. Some approaches have provided promising results. However, some unique characteristics of the HMGA proteins have not been exploited; these include their extensive protein-protein interaction network and their intrinsically disordered status that present the possibility that HMGA proteins could be involved in the formation of proteinaceous membrane-less organelles (PMLO) by liquid-liquid phase separation. These unexplored characteristics could open new pharmacological avenues to counteract the oncogenic contributions of HMGA proteins.

KEYWORDS:

• High Mobility Group A
• anticancer therapies
• stemness
• chemoresistance
• breast cancer
• HMGA1
• HMGA2

Article highlights

• Triple-negative breast cancer (TNBC) is the most difficult breast cancer subtype to treat because of its heterogeneity and lack of specific therapeutic targets.

• HMGA proteins are chromatin architectural factors that have oncogenic functions in breast cancer. They are promising molecular therapeutic targets for this disease.

• HMGA proteins are largely involved in stemness maintenance which is associated with chemoresistance acquisition.

• HMGA proteins have a relevant role in the cancer chemotherapy response, but further studies are necessary to define the role of HMGA proteins in cancer chemoresistance/sensitization.

• There are different strategies to target HMGA proteins in breast cancer and new ones could be developed.

• Two opportunities exist: a) to develop already consolidated strategies to counteract HMGA activities that could receive a strong impulse from recent developments in molecular structural modelling and delivery strategies; b) follow novel and unexplored directions, i.e., the possibility to interfere with HMGA’s protein-protein interaction network and with their peculiar biophysical properties that should confer to these proteins the ability to be intrinsically disordered proteins involved in the formation of proteinaceous membrane-less organelles (PMLO).

This box summarizes key points contained in the article.

Acknowledgments

We thank all the former members of our laboratory for their contribution in investigating the role of HMGA proteins in breast cancer.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

The research of the authors was funded by Associazione Italiana per la Ricerca sul Cancro (AIRC, IG18385) and Regione Friuli Venezia Giulia (TNBCneo) to GM.