Transcription factors drivers of malignancy and progression in breast cancer

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Background

Breast cancer (BC) is the most diagnosed cancer in females worldwide and one of the leading causes of cancer deaths. BC is a heterogeneous disease composed of different BC subtypes with distinct molecular characteristics and genetic profiles: Normal-like, Luminal A, Luminal B, Human epidermal growth factor receptor 2 (HER2)-enriched and basal-like subtypes. Nearly overlapping with basal-like BCs, there are triple-negative BCs, which lack expression of estrogen receptor (ER), progesterone receptor (PR), and HER2. TNBCs are among the most aggressive BCs, presenting a higher 5-year mortality rate after treatment compared to other BCs.

Recent comprehensive analyses across cell types and cancer types have outlined a vast network of protein-protein associations between transcription factors. Not surprisingly, protein-protein networks central to oncogenesis and disease progression are highly altered during breast cancer pathogenesis. Overexpression and gain-of-function mutations in oncogenic transcription factors have shown to promote malignancy and progression of breast cancer through the activation of oncogenic programs, such as uncontrollable proliferation, epithelial-to-mesenchymal transition, stemness, drug and radiotherapy resistance, angiogenesis and metastasis. Examples of transcription factors playing a crucial role in those processes are ER, PR, p53, ENGRAILED 1, SOX2, MYC, BCL11A, HIFα, MCL1 and ZEB1. At the clinical level, the immunodetection of transcription factors on tumor specimens is part of routine testing and plays a role in making further clinical decisions. For instance, current biomarker determinations such as ER and PR expression guide treatment on BC patients. Nevertheless, more research in biomarker discovery is needed to accurately predict pathological complete response and patient outcomes, such as survival and progression risk.

From the therapeutic viewpoint, inhibiting the interactions between transcription factors represents a very significant challenge. Contact surfaces responsible for protein-protein interactions are relatively large and grooves or binding pockets minimal or absent. Consequently, the development of small-molecule inhibitors able to bind such featureless protein interfaces is extremely difficult. On the other hand, biologicals such as antibodies present a reduced membrane penetrability to bind and inhibit intracellular transcription factors. However, promising tools such as interference peptides, peptidomimetics, and engineered nanoparticles have emerged to offer a solution to the targeting problem. These therapeutics can further be linked to cell-penetrating peptides (CCP) to facilitate cellular internalization and enhance their therapeutic potential. CPP are usually short cationic or amphipathic peptides, able to interact with the negatively-charged biological membranes. One interesting natural compound acting as CPP is melittin which composes 50% of the dry weight of the honeybee venom and is able to induce apoptosis in cancer cells.

In this Research Topic, we aim to provide an overview of the recent advances in transcription factors relevant to breast cancer growth and progression and the development of different targeting approaches. We welcome Original Research articles, Reviews and Systematic Reviews covering but not limited to the following topics:

1. Discovery of novel transcription factors playing a role in breast cancer initiation and progression
2. Transcription factors as survival and prognosis-associated biomarkers for breast cancer in the clinic
3. Therapeutics targeting transcription factors in breast cancer: Cyclic peptides, peptide mimetics, small molecule inhibitors, antibodies and engineered nanoparticles, among others
4. Cell-penetrating peptides facilitating cellular internalization and/or inducing apoptosis in breast cancer
5. Clinical translation of transcription factor inhibitors for breast cancer

Keywords: Transcription factors, biomarkers, breast cancer, clinical trials, peptides, nanoparticles, melittin

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