There is mounting proof that the enzyme mitogen-activated protein kinase 4 (MAPK4), which is also known as extracellular-regulated kinase 4 (ERK4), contributes to tumor expansion and treatment resistance. Researchers from Baylor College of Medicine and other institutions recently published their findings that MAPK4 appears to play an important role in the development of triple negative breast cancer, a devastating cancer with very limited therapeutic options, in the international journal Nature Communications under the title "MAPK4 promotes triple negative breast cancer growth and reduces tumor sensitivity to PI3K blockade".

Scientists found that MAPK4 is overexpressed in many patients with triple-negative breast cancer by analyzing public genomic databases. They also found that silencing MAPK4 inhibited the growth of human triple-negative breast cancer cells in animal models and made cancer cells more sensitive to therapies that block the cancer-promoting PI3K signaling pathway. Research into whether targeting MAPK4 in triple-negative breast cancer can improve cancer therapy is encouraged by these findings.

"In this study, we combined two long-standing points of interest in the lab, namely studying the critical role of MAPK4 in human cancer and better understanding breast cancer, the most commonly diagnosed type of cancer worldwide," said researcher Feng Yang. In particular, the research in this paper focuses on triple-negative breast cancer, one of the most difficult to treat subtypes of breast cancer. The researchers first analyzed gene expression profiles in 817 human breast cancer samples from the Cancer Genome Atlas database, including multiple breast cancer subtypes, and found that MAPK4 expression is elevated in 30% and more of basal-like breast cancer subtypes (70%-80% of which are triple-negative breast cancer).

In addition, the researchers analyzed MAPK4 expression in a collection of breast cancer patient-derived xenografts (PDX) collected from Baylor Cancer Research Center, most of which were triple-negative breast cancers. In a large subset of PDX tumors, the researchers also found elevated MAPK4 expression. Previous findings suggest that MAPK4 plays a role in promoting cancer in other cancer types such as prostate cancer, and the finding that MAPK4 levels are elevated in an important subtype of triple-negative breast cancer may prompt researchers to investigate whether MAPK4 also promotes the development of triple-negative breast cancer.

Researchers experimented with MAPK4 gene expression. Cancer cell proliferation was dramatically inhibited when MAPK4 was eliminated by knockdown or knockout techniques, the study revealed. In low expressing triple negative breast tumors, researchers discovered that increasing MAPK4 levels led to tumor cell growth. These results lend credence to MAPK4's significance in driving the development of triple-negative breast cancer.

The molecular pathways by which MAPK4 promotes carcinogenesis in triple-negative breast cancer were later investigated by Yang and colleagues. Researchers have previously established that MAPK4 can activate a cancer-promoting signaling pathway in cells called AKT, and current research suggests that this may also be the case with triple-negative breast cancer.

"Triple-negative breast cancer activates AKT through two separate mechanisms, one mediated by MAPK4 and the other by an enzyme class called PI3K. We all know that alterations in the PI3K pathway are common in triple-negative breast cancer, but the therapeutic benefit of PI3K inhibitors is very limited, and in this paper, we propose a new mechanism that may help explain the lack of corresponding efficacy of the inhibitors," said researcher Yang.