“The estrogen receptor is overexpressed in and promotes 67-80% and 90% of female and male breast cancer cases, respectively.“
Most breast cancers depend on estrogen to grow. This dependence explains why hormone-based treatments, such as aromatase inhibitors, are among the most effective therapies for estrogen receptor–positive breast cancer. Despite their success, these treatments do not work indefinitely for all patients.
Over time, many tumors adapt to estrogen deprivation and continue to survive, grow, and spread. This process, known as aromatase inhibitor resistance, represents a major clinical challenge and is often associated with more aggressive disease and poorer outcomes.
One reason resistant breast tumors are difficult to treat is that cancer cells adapt their internal signaling systems. Instead of relying on estrogen, they activate alternative growth pathways, including the MAPK and PI3K/AKT pathways. These pathways promote cell survival, movement, and resistance to therapy and are frequently driven by proteins such as KRAS and related G-proteins, which have historically been difficult to target. A recent study published in Oncotarget suggests now that a new class of compounds may offer a way to overcome this resistance.
The Study: Targeting Aromatase Inhibitor–Resistant Breast Cancer with Novel PCAI Compounds
Researchers from the Florida A&M University College of Pharmacy and Pharmaceutical Sciences, Institute of Public Health, investigated a group of experimental compounds called polyisoprenylated cysteinyl amide inhibitors, or PCAIs. Their study, titled “PCAIs stimulate MAPK, PI3K/AKT pathways and ROS-mediated apoptosis in aromatase inhibitor-resistant breast cancer cells while disrupting actin filaments and focal adhesion,” focused on breast cancer cells that had developed resistance after long-term treatment with letrozole (LTLT-Ca cells), a commonly prescribed aromatase inhibitor.
The goal was to determine whether PCAIs could disrupt key survival mechanisms in these resistant cancer cells and ultimately trigger cell death.
The Results: NSL-YHJ-2-27 Activates MAPK and PI3K/AKT Pathways to Induce Apoptosis in Resistant Breast Cancer Cells
Among the tested compounds, one PCAI, NSL-YHJ-2-27, showed strong effects. Treatment with this compound significantly reduced the survival of aromatase inhibitor-resistant breast cancer cells and caused changes in cell shape. Many cells shrank, rounded up, and detached from their growth surface. Even after the compound was removed, treated cells showed a markedly reduced ability to proliferate and form colonies, indicating long-lasting effects.
At the molecular level, NSL-YHJ-2-27 increased activation of MAPK and PI3K/AKT signaling pathways. While these pathways are often associated with cancer cell survival, their excessive activation in this context led to cellular stress rather than protection. The treatment also caused a rise in reactive oxygen species, highly reactive molecules that damage DNA, proteins, and lipids inside the cell.
In addition, NSL-YHJ-2-27 reduced the levels of key proteins involved in cell movement and structure, including RAC1 and CDC42. The compound disrupted actin filaments and decreased levels of focal adhesion proteins such as vinculin and fascin, weakening the cells’ internal framework. As a result, cancer cell migration and invasion were significantly reduced in both standard cell cultures and three-dimensional tumor-like spheroids. The treated cells also showed clear signs of apoptosis, confirming that the compound effectively triggered programmed cell death.
The Breakthrough: Targeting Cancer Cells from Within to Trigger Stress-Induced Cell Death
Rather than blocking signals at the cell surface, PCAIs act inside cancer cells by interfering with proteins that control growth, movement, and survival. By disrupting these internal systems, PCAIs place cancer cells under intense stress. This stress leads to the buildup of reactive oxygen species and ultimately leads the cells toward self-destruction.
The Impact: A Potential New Therapeutic Strategy for Hormone-Resistant Breast Cancer
These results suggest that PCAIs could represent a potential new strategy for treating breast cancers that no longer respond to hormone therapy. Because this approach does not rely on estrogen receptors or specific surface markers, it may be effective across a broader range of resistant tumors. Importantly, by weakening the structural and migratory machinery of cancer cells, PCAIs may also reduce the ability of tumors to spread to other organs.
Future Perspectives and Conclusion
Although this research was conducted using laboratory models, it provides a solid foundation for further investigation. Additional studies will be required to evaluate safety, determine appropriate dosing, and assess the effects of PCAIs in animal models and, ultimately, in clinical settings. While still at an early stage, these findings suggest a possible new approach for addressing hormone therapy resistance in breast cancer. With continued research, PCAIs may contribute to the development of additional therapeutic options for patients with treatment-resistant disease.
Click here to read the entire research paper published by Oncotarget.
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Oncotarget is an open-access, peer-reviewed journal that has published primarily oncology-focused research papers since 2010. These papers are available to readers (at no cost and free of subscription barriers) in a continuous publishing format at Oncotarget.com.
Oncotarget is indexed and archived by PubMed/Medline, PubMed Central, Scopus, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science).
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