A groundbreaking review published in Oncotarget on March 13, 2025, illuminates how disruptions in cellular communication within breast cancer cells contribute to treatment resistance. This research, spearheaded by Dinara Ryspayeva and her team at Brown University, meticulously examines the signaling pathways that enable tumors to thrive, spread, and evade conventional therapies. The findings hold significant promise for developing more effective and personalized treatment strategies for this prevalent disease, which affects millions of women across the United States.

Breast cancer remains the most common cancer among women in the U.S., second only to skin cancers, and a leading cause of cancer-related deaths. The American Cancer Society estimates that in 2024, approximately 310,720 new cases of invasive breast cancer were diagnosed in women, and about 42,250 women succumbed to the disease. While advancements in treatment have substantially improved survival rates, a significant number of patients still experience recurrence or develop resistance to therapy. This new review delves into the molecular mechanisms behind these challenges, offering hope for overcoming them.

The core issue, according to the review, lies in the dysregulation of signaling pathways within breast cancer cells. These pathways are complex networks of proteins that control essential cellular functions such as growth, division, DNA repair, and survival. When these pathways are disrupted by genetic mutations or other alterations, they can fuel tumor progression and resistance to treatment. Understanding these disruptions is crucial for developing targeted therapies that can effectively shut down these aberrant signals.

key Signaling Pathways and Their Role in Breast Cancer

The review identifies several major signaling pathways that are frequently implicated in breast cancer progress and progression. These include:

• PI3K/Akt/mTOR: This pathway is a central regulator of cell growth and metabolism. In many breast cancers, notably hormone receptor-positive and HER2-positive subtypes, it becomes hyperactive due to gene mutations or the loss of PTEN, a tumor-suppressing protein.
• RAS/RAF/MEK/ERK: this pathway plays a critical role in cell proliferation and differentiation. Even in the absence of mutations, it can become activated when other primary pathways are blocked, especially in HER2-positive and triple-negative breast cancers.
• HER2: The HER2 pathway is crucial in certain breast cancer types. Overexpression of HER2 leads to increased cell proliferation and tumor growth.
• Wnt/β-catenin: This pathway is involved in cell fate determination and tissue development. Aberrant activation can promote tumor growth and metastasis.
• Notch: the Notch pathway regulates cell differentiation and proliferation. Its dysregulation has been implicated in breast cancer stem cell maintenance and drug resistance.
• NF-κB: This pathway is a key regulator of inflammation and immune responses. In breast cancer, it can promote tumor survival and metastasis.
• DNA Damage Response (DDR): This pathway is responsible for repairing damaged DNA. Defects in DDR can lead to genomic instability and increased cancer risk.

The PI3K/Akt/mTOR pathway, in particular, stands out as a frequent culprit in treatment resistance. As the authors note, “Up to 25–40% of BC cases exhibit variations that hyperactivate the PI3K/Akt/mTOR pathway, underscoring its critical role in oncogenesis.” This overactivation can lead to uncontrolled cell growth and proliferation, making tumors more aggressive and less responsive to conventional therapies like chemotherapy and hormone therapy.

Consider the case of hormone receptor-positive breast cancer, the most common subtype. These cancers rely on estrogen to fuel their growth. While drugs like tamoxifen, which block estrogen receptors, are frequently effective initially, many tumors eventually develop resistance. Overactivation of the PI3K/Akt/mTOR pathway is a major mechanism behind this resistance, allowing cancer cells to bypass the estrogen blockade and continue growing. This is akin to a car’s engine finding a way to run even when the fuel line is supposedly cut off.

Emerging Treatments and Clinical Trials

The review highlights the development of new and emerging treatments specifically designed to target these disrupted signaling pathways. These targeted therapies aim to block the aberrant signals that drive tumor growth and resistance, offering a more precise and effective approach to cancer treatment.

Several drugs targeting these pathways are already approved for use in certain breast cancer subtypes. For example, PI3K inhibitors like alpelisib have been approved for hormone receptor-positive, HER2-negative breast cancer patients with PIK3CA mutations. Similarly, HER2-targeted therapies like trastuzumab and pertuzumab have revolutionized the treatment of HER2-positive breast cancer.These drugs act like targeted missiles,hitting specific vulnerabilities in the cancer cells while sparing healthy tissue.

However, many other promising therapies are still in clinical trials. These include:

PARP inhibitors, as an example, have shown remarkable success in treating breast cancers with BRCA1 or BRCA2 mutations, which impair the DNA Damage Response pathway. These drugs prevent cancer cells from repairing damaged DNA, leading to their death. This is a prime example of precision medicine, where treatments are tailored to the specific genetic makeup of the tumor.

Implications for the Future of Breast Cancer Treatment

The findings from this review have profound implications for the future of breast cancer treatment. By gaining a deeper understanding of the signaling pathways that drive tumor growth and resistance, researchers can develop more effective and personalized therapies.This includes:

• Personalized medicine: Tailoring treatment strategies to the specific genetic and molecular characteristics of each patient’s tumor.
• Combination therapies: Combining targeted therapies with conventional treatments to overcome resistance and improve outcomes.
• Early detection: Identifying biomarkers that can predict treatment response and resistance, allowing for earlier intervention and more effective treatment planning.
• Prevention strategies: Developing strategies to prevent the development of breast cancer in high-risk individuals by targeting key signaling pathways.

The development of liquid biopsies, which can detect circulating tumor DNA in the blood, is another promising area. These biopsies can provide real-time information about the genetic makeup of the tumor and its response to treatment, allowing doctors to adjust therapy as needed.This is like having a continuous monitoring system that tracks the cancer’s behavior and guides treatment decisions.

Moreover, understanding these cellular communication breakdowns could lead to innovative preventative measures. For women with a high genetic risk, interventions targeting these pathways might delay or even prevent the onset of breast cancer. This proactive approach could significantly reduce the overall burden of the disease.

Breast Cancer Breakthroughs: Decoding Cellular Signals to Conquer Treatment Resistance – An Exclusive Interview

To further explore these groundbreaking findings, consider this hypothetical interview with a leading oncologist:

Interviewer: “Dr. Emily Carter, thank you for joining us. this review highlights the critical role of cellular signaling in breast cancer treatment resistance. Can you elaborate on why this is such a significant breakthrough?”

Dr. Carter: “Absolutely. For years, we’ve been treating breast cancer with broad-spectrum therapies like chemotherapy and hormone therapy. While these treatments can be effective initially, many tumors eventually develop resistance. This review sheds light on the underlying mechanisms behind this resistance, allowing us to develop more targeted and effective therapies. It’s like finally understanding the enemy’s communication codes, allowing us to disrupt their plans.”

Interviewer: “What are some of the most promising emerging treatments that target these signaling pathways?”

Dr. Carter: “We’re seeing great progress with drugs that target the PI3K/Akt/mTOR pathway,as well as HER2-targeted therapies. PARP inhibitors have also been a game-changer for patients with BRCA mutations. But the real excitement lies in the development of new therapies that target other key signaling pathways, such as Wnt/β-catenin and Notch. These drugs are still in clinical trials, but they hold tremendous promise for overcoming treatment resistance and improving outcomes.”

Interviewer: “What advice would you give to breast cancer patients and their families who are facing treatment resistance?”

Dr. Carter: “First and foremost, don’t lose hope. Research is advancing at an astonishing pace, and new treatments are constantly being developed. Talk to your doctor about the possibility of participating in clinical trials, which can provide access to cutting-edge therapies. Also, focus on maintaining a healthy lifestyle, including a balanced diet, regular exercise, and stress management. These factors can play a significant role in your overall well-being and response to treatment.”

The fight against breast cancer is far from over, but this new understanding of cellular signaling pathways offers a beacon of hope. By targeting these pathways with precision therapies, we can overcome treatment resistance and improve the lives of millions of women affected by this devastating disease. The future of breast cancer treatment is personalized, targeted, and ultimately, more effective.