Signaling pathway dysregulation in breast cancer

Abstract

This article provides a comprehensive analysis of the signaling pathways implicated in breast cancer (BC), the most prevalent malignancy among women and a leading cause of cancer-related mortality globally. Special emphasis is placed on the structural dynamics of protein complexes that are integral to the regulation of these signaling cascades. Dysregulation of cellular signaling is a fundamental aspect of BC pathophysiology, with both upstream and downstream signaling cascade activation contributing to cellular process aberrations that not only drive tumor growth, but also contribute to resistance against current treatments. The review explores alterations within these pathways across different BC subtypes and highlights potential therapeutic strategies targeting these pathways. Additionally, the influence of specific mutations on therapeutic decision-making is examined, underscoring their relevance to particular BC subtypes. The article also discusses both approved therapeutic modalities and ongoing clinical trials targeting disrupted signaling pathways. However, further investigation is necessary to fully elucidate the underlying mechanisms and optimize personalized treatment approaches.

Keywords: breast cancer; clinical trials; oncogenic pathways; signal dysregulation in cancer; therapeutic approaches.

Figure 1. Key signaling pathways and targeted factors in dysregulated BC.

This figure illustrates the major signaling pathways and their intricate crosstalk in BC, focusing on the GPCR, RTKs, RAS/RAF/MEK1/2/ERK1/2, MAPK, HER2, PI3K/Akt/mTOR, Wnt/β-catenin, NF-κB, Notch, and DDR pathways. These pathways are critical in regulating essential cellular processes such as proliferation, survival, differentiation, and metastasis. The MAPK pathway, initiated by RTKs like EGFR and HER2, activates downstream effectors such as RAS, RAF, MEK, and ERK1/2, driving cell growth and survival. HER2 amplification further drives oncogenesis by activating the MAPK and PI3K/Akt pathways, with HER3 and HER4 modulating these signals. The PI3K/Akt/mTOR pathway controls cell growth and metabolism through Akt activation and downstream targets like mTORC1/2, p70S6K1, and 4E-BP1. Mutations in PIK3CA and loss of PTEN contribute to its hyperactivation. The Wnt/β-catenin pathway promotes EMT and metastasis, driven by Wnt signaling through LRP5/6 and β-catenin, which interact with APC, CKIα, and TCF/LEF. The NF-κB pathway is a central signaling network regulating inflammation, immune responses, and cell survival. This pathway is activated through Tumor Necrosis Factor Receptors (TNFR), Toll-like Receptors (TLRs), and the IκB kinase (IKK) complex. The Notch pathway, triggered by receptor-ligand interactions between Notch receptors and ligands like DLL, governs cell fate determination and contributes to cancer progression by promoting proliferation and maintaining cancer stem cells. The DDR pathway is essential for maintaining genomic stability by detecting and repairing DNA damage. It responds to various types of damage, including DSBs, SSBs, and cross-links, by activating repair mechanisms such as HR for DSBs and NER to other kinds of damage. In BC, dysregulation of the DDR pathway, often due to mutations in genes like BRCA1 and BRCA2, impairs DNA repair, leading to genomic instability and an increased risk of cancer.