Mapk4 May Be a New Target for the Treatment of Triple-Negative Breast Cancer

There is now growing evidence that the MAPK4 enzyme may be involved in cancer growth and resistance to specific therapies.

Recently, an article titled " MAPK4 promotes triple negative breast cancer growth and reduces tumor sensitivity to PI3K blockade" was published in Nature Communications.

By analyzing public genome databases, the researchers found that a large number of triple-negative breast cancer patients express high levels of MAPK4, and in animal models, elimination of MAPK4 reduced the growth of human triple-negative breast cancer cells and made cancer cells resistant to blocking PI3K.

The discovery of PI3K, a signaling pathway that promotes cancer growth, supports further research by scientists to investigate whether targeting MAPK4 in triple-negative breast cancer could improve cancer treatment.

"In this study, we combined two longstanding interests of our laboratory, namely to study the critical role that MAPK4 plays in human cancer, and to better understand breast cancer, the most common disease worldwide," said Feng Yang, one of the researchers. The study specifically focused on triple-negative breast cancer, one of the most difficult-to-treat breast cancer subtypes.

First, the researchers 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 was elevated in 30% and more basal-like breast cancer subtypes (70% – 80% of which were triple-negative breast cancers).

In addition, the researchers analyzed MAPK4 expression in a collection of breast cancer patient-derived xenografts (PDX) from Baylor Cancer Research Center, most of which were triple-negative breast cancers. PDX refers to an animal model of human cancer that closely reproduces cancer in humans. Physically, the researchers also found elevated MAPK4 expression in PDX tumors in triple-negative breast cancer.

Previous studies have shown that MAPK4 plays a role in promoting carcinogenesis in other cancers, such as prostate cancer, and the discovery of important subtypes of triple-negative breast cancer with elevated MAPK4 levels may prompt researchers to investigate whether MAPK4 can also promote the development of triple-negative breast cancer.

In seven different human triple-negative breast cancer cell lines, some had high and some had low MAPK4 expression, and the researchers manipulated the gene expression level of MAPK4 when MAPK4 was knocked down or eliminated by the knockout method. The researchers found that the growth of cancer cells slowed significantly, suggesting that MAPK4 plays an important role in the development of triple-negative breast cancer.

The researchers also increased MAPK4 levels in low-expressing triple-negative breast cancers, which in turn boosted cancer cell growth, a finding that supports a critical role for MAPK4 in triple-negative breast cancer growth.

Subsequently, Yang and his colleagues investigated the tumor-promoting molecular mechanism of MAPK4 in triple-negative breast cancer. Previously, researchers found that MAPK4 may promote the development of other cancers by activating a cancer-promoting signaling pathway in cells called AKT.

Triple-negative breast cancer can activate AKT through two independent mechanisms, one mediated by MAPK4 and the other by an enzyme called PI3K. "We all know that alterations in the PI3K pathway are very common in triple-negative breast cancer, but the therapeutic effect of PI3K inhibitors is very limited," said researcher Yang.

The researchers noted that inhibiting PI3K may allow cells to activate AKT through MAPK4, allowing cells to continue to grow; to confirm this idea, the researchers found that knocking out MAPK4 may cause cells to become sensitive to PI3K inhibitors and reduce cancer growth. In addition, in low-expressing triple-negative breast cancer, overexpression of MAPK4 may make cells resistant to the effects of PI3K inhibitors and continue to promote their growth.

The researchers say the study in this paper may provide new therapeutic opportunities for triple-negative breast cancer based on MAPK4 expression, which could include a new combination of inhibitors to help control cancer growth, although this may require further research.

Taken together, the study suggests that high MAPK4 expression may define a large subset or subtype of triple-negative breast cancers that respond to MAPK4 blockade, while targeting subsets/subtypes of triple-negative breast cancer that act on MAPK4 not only inhibits tumor growth, but also makes tumors more sensitive to PI3K blockade.