Researchers Identify Key Signaling Pathway Disruptions Driving Breast Cancer Treatment Resistance

Researchers from Brown University discover that disruptions in signaling pathways, namely PI3K/Akt/mTOR, drive oncogenesis and poor treatment responses in breast cancer (BC). Their findings, published in Oncotarget, may provide a deeper look into the mechanisms underlying drug responses, thereby improving care for patients with aggressive or hard-to-treat BC subtypes.¹

Breast cancer cells | Image Credit: © Wasana - stock.adobe.com

BC is the most common cancer amongst women, accounting for approximately 30% of new female cancers each year. Despite advancements in treatment that extend beyond surgery, hormone therapy, or chemotherapy, many patients with BC experience recurrence of disease and may stop responding to subsequent treatments. This is especially true for patients with BC subtypes, including estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 types. Treatment challenges in BC therapy highlight the critical need for not just developing new agents and therapeutic approaches but also understanding the mechanisms underlying disease progression and treatment responses.^1-3

"Innovations in therapeutic strategies, coupled with a deeper understanding of [BC] biology, will be essential for advancing personalized medicine and improving clinical outcomes,” Dinara Ryspayeva, PhD, medical oncologist and visiting assistant professor at Brown University, said.³

A key component of the pathophysiology of BC is the dysregulation of cellular signaling, with the activation of both upstream and downstream signaling cascades causing cellular process abnormalities that not only promote tumor growth but also increase resistance to existing therapies. Ryspayeva and her colleagues performed a comprehensive analysis of the major signaling pathways associated with BC and identified various that control cell growth, division, DNA repair, and survival. These included PI3K/Akt/mTOR, RAS/RAF/MEK/ERK, HER2, Wnt/β-catenin, Notch, NF-κB, and the DNA damage response (DDR).^1,3

The researchers found that PI3K/Akt/mTOR was the most disrupted of the signaling pathways. It plays a substantial role in regulating cell growth, proliferation, metabolism, and survival through the activation of Akt and downstream targets such as mTORC1/2, p70S6K1, and 4E-BP1. PI3K/Akt/mTOR hyperactivation is caused by PTEN depletion, which results in sustained pathway activation and cancer progression, and PIK3CA mutations.

“Up to 25% to 40% of BC cases exhibit variations that hyperactivate the PI3K/Akt/mTOR pathway, underscoring its critical role in oncogenesis,” Ryspayeva said in the news release.³

Another key pathway they identified was RAS/RAF/MEK/ERK. The RAS/RAF/MEK/ERK pathway, a key signaling route often altered in cancer, is generally considered infrequently mutated in BC. However, advanced molecular techniques have revealed that non-genetic activation of this pathway plays a crucial role in BC. When the RAS/RAF/MEK/ERK pathway is dysregulated in cancer, its signal amplification can make oncogenic effects worse.¹

The authors highlighted emerging treatments in BC, focusing on targeted therapies, immunotherapies, and novel drug delivery systems to overcome resistance and improve precision targeting. Key innovations include antibody-drug conjugates, degrader-antibody conjugates, bispecific antibodies, experimental vaccines, and therapies targeting DDR pathways like PARP inhibitors.¹

These advances, along with epigenetic treatments and theranostics for real-time monitoring, offer the potential for more personalized and effective BC therapies. Continued research into these pathways is crucial for developing combination therapies that improve clinical outcomes and advance personalized medicine.¹

REFERENCES

1. Ryspayeva D, Seyhan A, Macdonald W, et al. Signaling pathway dysregulation in breast cancer. Oncotarget. March 13, 2025. doi.org/10.18632/oncotarget.28701

2. Key statistics for breast cancer. American Cancer Society. January 22, 2025. Accessed March 26, 2025. https://www.cancer.org/cancer/types/breast-cancer/about/how-common-is-breast-cancer.html

3. Why some breast cancer treatments stop working. News Release. March 25, 2025. Accessed March 26, 2025. https://www.eurekalert.org/news-releases/1078075