image: 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.
Credit: Copyright: © 2025 Ryspayeva et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
"Innovations in therapeutic strategies, coupled with a deeper understanding of breast cancer biology, will be essential for advancing personalized medicine and improving clinical outcomes.”
BUFFALO, NY - March 25, 2025 – A new review was published in Oncotarget, Volume 16, on March 13, 2025, titled “Signaling pathway dysregulation in breast cancer."
In this review article, Dinara Ryspayeva and colleagues from Brown University provide a detailed look at how breast cancer cells change the way they communicate and grow—helping tumors survive, spread, and resist treatment. The review highlights how certain gene mutations and disrupted signaling pathways influence therapy response across different types of breast cancer. It also outlines current treatment strategies and clinical trials, offering insights that could improve care for patients with aggressive or hard-to-treat cancers.
Breast cancer is the most common cancer in women and a major cause of cancer-related deaths worldwide. While many patients respond to treatment at first, some cancers return or stop responding. The review explores how signaling disruptions inside tumor cells are often behind these setbacks.
The authors discuss several major pathways involved in breast cancer, including PI3K/Akt/mTOR, RAS/RAF/MEK/ERK, HER2, Wnt/β-catenin, Notch, NF-κB, and the DNA damage response (DDR). These pathways help control cell growth, division, DNA repair, and survival. When altered by mutations or other changes, they can promote tumor progression and resistance to treatment.
One of the most disrupted pathways is PI3K/Akt/mTOR. It plays a central role in cell growth, but in many breast cancers—especially hormone receptor-positive and HER2-positive types—it becomes overactive due to gene mutations, or the loss of a tumor-suppressing protein called PTEN.
“Up to 25–40% of BC cases exhibit variations that hyperactivate the PI3K/Akt/mTOR pathway, underscoring its critical role in oncogenesis.”
Another key pathway, RAS/RAF/MEK/ERK, can also promote tumor growth. Even without mutations, it may become active when primary pathways are blocked, particularly in HER2-positive and triple-negative breast cancers.
The review also highlights several new and emerging treatments aimed at blocking down these signaling pathways. Some drugs are already approved, while others are in clinical trials. The authors suggest that combining different treatments may help stop multiple pathways at once, making it harder for cancer cells to adapt. Matching treatments to each tumor’s unique genetic changes could also improve patient outcomes.
This comprehensive review gives researchers and clinicians a clearer understanding of how breast cancer resists treatment and where future therapies should focus. A better understanding of these disrupted signaling systems could lead to more personalized and effective treatments for patients facing aggressive or recurring disease.
Continue reading: DOI: https://doi.org/10.18632/oncotarget.28701
Correspondence to: Dinara Ryspayeva — dinara_ryspayeva@brown.edu
Keywords: cancer, breast cancer, oncogenic pathways, signal dysregulation in cancer, therapeutic approache, clinical trials
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Journal
Oncotarget
Method of Research
Systematic review
Subject of Research
Cells
Article Title
Signaling pathway dysregulation in breast cancer
Article Publication Date
13-Mar-2025
COI Statement
WED is the scientific founder and shareholder of Oncoceutics Inc. (acquired by Chimerix), p53-Therapeutics Inc., and SMURF-Therapeutics Inc. El-Deiry has disclosed his relationship with Oncoceutics/Chimerix and potential conflict of interest to his academic institution/employer and is fully compliant with the NIH and the institutional policy that is managing this potential conflict of interest.