New insights into therapy resistance in breast cancer

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.