The tumor microenvironment is comprised of a variety of different components that includes immune cells, which are part of the body’s natural defenses against infection. However, the role that the tumor microenvironment plays in tumor growth and progression is not yet completely understood. Researchers are working to understand how to modulate or engage specific immune cells already present near tumor cells to work against them. This strategy, called immunotherapy, has been successful in some cancers but less so in breast cancer. However, immunotherapy has shown some promise in treating triple-negative breast cancer (TNBC), an aggressive subtype of breast cancer with few treatment options.
BCRF investigator Dr. Jean Zhao conducts research focused on integrating immunotherapy and targeted therapy to “break through” cancer, particularly for difficult-to-treat breast cancers like TNBC. In a recent article published in Nature, Dr. Zhao describes how her team targeted a pathway involving a pair of protein molecules that oppose each other’s activity in tumor cells—PTEN and PI3Kβ—and how they may be leveraged to improve immunotherapy outcomes in breast cancer.
The phosphatase and tensin homolog (PTEN) gene encodes the instructions for making an enzyme of the same name that is found in almost all tissues of the human body. The PTEN enzyme is a phosphatase that functions as a tumor suppressor, which means it keeps cells from growing and dividing rapidly or uncontrollably, a hallmark of cancer.
Those who have inherited PTEN mutations have a four-fold higher lifetime risk of developing breast cancer than those who are at average risk, which is similar to the risk profiles associated with mutations in the BRCA1/2 genes. Patients with breast cancer carrying a PTEN mutation are at increased risk of endometrial, thyroid, kidney, and colorectal cancers as well as a second breast cancer.
The loss of the phosphatase resulting from the PTEN gene mutation activates the enzyme PI3Kβ, a kinase that governs signaling activity and can cause tumor cells to proliferate when left unchecked by the PTEN phosphatase. By using state-of-the-art PTEN-deficient breast cancer laboratory models designed by her research team, Dr. Zhao discovered that PI3Kβ activation promotes not just a pathway that fuels cancer proliferation but also controls a pathway that blocks the body’s natural immune defenses to suppress tumor growth.
They further discovered that when a PTEN-deficient tumor was treated with an inhibitor of PI3Kβ or another protein called STAT3 (also involved in the pathway controlling the suppression of the immune system), a variety of immune cells were recruited to the tumor environment and led to destruction of tumor cells and shrinking of the tumor. When this inhibitor was combined with a pharmacological immunotherapy, breast tumors were eradicated in the research team’s breast cancer models.
These findings from Dr. Zhao and her team provide scientists with a blueprint on which to base strategies to target specific molecules, pathways, and mechanisms involved in cancer progression caused by mutations in the genetic code. Already, inhibitors of PI3Kβ are being investigated in early clinical trials in those with PTEN deficiencies and are showing potential in terms of safety and preliminary efficacy. In addition, this work may open doors for the development of immunotherapy strategies that have historically been more challenging to employ in breast cancer treatments.
The absence of the PTEN is a common driver across many different types of cancers, and those with the inherited mutation have an 85 percent lifetime risk of developing any cancer. Furthermore, the PTEN mutation is associated with a cancer diagnosis at a younger age. For people who have tested positive for a PTEN mutation, consulting a genetics expert or counselor to assess their personal and family history and assist in creating a plan to manage cancer risk may be recommended.
The insights gained from Dr. Zhao’s research will have an impact not just on breast cancer but on understanding of the fundamentals across several PTEN-deficient cancers. Her discoveries add to the growing knowledge that will help researchers develop the most effective and promising treatment strategies for the most challenging-to-treat cancers that arise as a result of these critical genetic mutations.
References:
“PI3Kβ controls immune evasion in PTEN-deficient breast tumours” Nature 617, 139-146 (2023)
“Breast cancer risk and clinical implications for germline PTEN mutation carriers” Breast Cancer Research and Treatment 165, 1-8 (2017)
“PTEN-deficient cancers depend on PIK3CB” Proceedings of the National Academy of Sciences 105 (35) 13057-13062 (2008)
“Cancer Risk Associated with PTEN pathogenic variants identified using multigene hereditary cancer panel testing” JCO Precision Oncology 7 (2023) e2200415
“Lifetime cancer risks in individuals with germline PTEN mutations” Clinical Cancer Research 18 (2): 400-407 (2012)
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