Breast cancer is one of the most common cancers among American women. It is estimated that within the United States, about 300,000 new cases will be diagnosed in 2025. The average risk of a woman getting breast cancer is 13%. However, many different factors can influence risk, including family history, environmental exposures, diet, and genetic predispositions. Unfortunately, breast cancer is the second leading cause of death in women. There are many different subtypes of breast cancer, and this also influences prognosis. More aggressive breast cancer types are referred to as “invasive”. Many are hormonally driven and require hormone therapy in combination with other targeted treatment or chemotherapy. Triple negative breast cancer (TNBC) is also an aggressive subtype which usually lacks specific receptors that are common breast cancer targets. The lack of effective surface markers to target and the rapid proliferation of this subtype is why it is so aggressive.
In addition to breast cancer proliferation, cells around the tumor also drive tumor growth. As breast cancer grows, it can evade the immune system by altering healthy immune cells. Consequently, these polarized immune cells will suppress other anti-tumor cells and promote cancer progression. Various immune cells make up the environment around the tumor known as the ‘tumor microenvironment’ (TME). The complexity and heterogeneity of cells limits therapeutic efficacy. Additionally, altered pro-tumor cells also allow the tumor to spread to other parts of the body, referred to as metastasis. Unfortunately, metastasis is a key prognostic factor that dictates treatment regimen. Currently, the standard-of-care for metastatic TNBC is surgery and chemotherapy in combination with an immunotherapy. Physicians will tailor treatment based on each patient to optimize therapeutic outcomes. Scientists are still working to learn more about metastatic TNBC and how the healthcare field can better target tumors to stop progression.
A recent article in the Proceedings of the National Academy of Sciences (PNAS), by Dr. Mitsuyasu Kato and others, found that a surface marker protein on TNBC cells drives pro-tumor immune cell function, which leads to metastasis. Kato is Executive Director and Professor at the University of Tsukuba in Japan. His work focuses on the immune system in the context of cancer and how it is regulated. Specially, Kato works to redirect the immune system toward the tumor and limit growth.
Kato and his team identified a specific surface protein on TNBC cells known as glycoprotein non-metastatic melanoma protein B (GPNMB). This protein is highly expressed and was found to reprogram macrophages, a critical antitumor immune cell type, to promote tumor growth. GPNMB alters macrophage function so they can no longer target the tumor but become tumor-associated macrophages (TAMs). This mechanism alters macrophage activity by GPNMB binding to macrophages through their surface receptor, sialic acid-binding immunoglobulin-type lectin 9 (Siglec-9). Researchers found that GPNMB or Siglec-9 inhibition can suppress tumor progression and sensitize tumor to other therapies. Thus, the GPNMB-Siglec-9 axis is a potential target for novel alternative TNBC therapy. Overall, this work provides a solution to TNBC therapeutic resistance and tumor metastasis. As further research works to demonstrate strong efficacy in the clinic, patients may have a new option for therapy that will improve quality of life and prolong patient survival.
