MAPK4 may serve as a novel therapeutic target for human triple-negative breast cancer

There is mounting evidence that the enzyme MAPK4 is involved in cancer growth and resistance to specific therapies. Researchers from Baylor College of Medicine and other institutions discovered 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 a recent study published in the international journal Nature Communications titled "MAPK4 promotes triple-negative breast cancer growth and reduces tumor sensitivity to PI3K blockade".

The researchers discovered that a large number of triple-negative breast cancer patients have high levels of MAPK4, and that removing MAPK4 reduced the growth of human triple-negative breast cancer cells in animal models and made cancer cells more sensitive to therapies that block PI3K, a signaling pathway that promotes cancer growth. The findings lend support to future research into whether cancer therapies can be improved by targeting MAPK4 in triple-negative breast cancer.

"In this study, we combined two of the lab's long-standing research interests in studying the key role MAPK4 plays in human cancer and in better understanding breast cancer, the most commonly diagnosed type of cancer worldwide, and in particular, this study focuses on triple-negative breast cancer, one of the most difficult to treat subtypes of breast cancer," said researcher Feng Yang. They 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 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 the animal model of human cancer that closely recapitulates the cancerous condition of the human organism. In a large subset of PDX with triple-negative breast cancer, researchers also found elevated expression of MAPK4 in them. Previous research suggests that MAPK4 promotes cancer development in other cancer types, such as prostate cancer, and the discovery that MAPK4 levels are elevated in an important subtype of triple-negative breast cancer may prompt researchers to investigate whether MAPK4 promotes the development of triple-negative breast cancer.

The researchers then manipulated the gene expression levels of MAPK4 in seven different human triple-negative breast cancer cell lines, some of which overexpressed MAPK4 and some of which underexpressed MAPK4, and when MAPK4 was eliminated by knockdown or knockout methods, the researchers discovered that the cancer cells' growth was significantly slowed. This would imply that MAPK4 is involved in the development of triple-negative breast cancer. In addition, the researchers increased the level of MAPK4 in triple-negative breast cancers with low expression, which promoted cancer cell growth. These findings support MAPK4's critical role in the progression of triple-negative breast cancer.

The researchers then investigated the molecular mechanisms underlying MAPK4's carcinogenesis promotion in triple-negative breast cancer. Previously, it was discovered that MAPK4 can promote the growth of other cancer types by activating a cancer-promoting signaling pathway called AKT in cells. The current study discovered that this may also be the case in triple-negative breast cancer. Triple-negative breast cancer can activate AKT via two distinct pathways, one mediated by MAPK4 and the other by an enzyme class known as PI3K.

The researchers noted that inhibiting PI3K may allow the cells to potentially activate AKT via MAPK4, allowing the cells to grow. It was discovered that knocking out MAPK4 causes cells to become more sensitive to PI3K inhibitors and can slow cancer growth. Furthermore, MAPK4 overexpression in triple-negative breast cancers with low expression may allow the cells to resist the effects of PI3K inhibitors and continue to grow.

This study may provide a novel therapeutic opportunity based on MAPK4 expression in triple-negative breast cancer, which may include a novel combination of inhibitors to help control cancer's growth, though further research at a later stage may be required to confirm this idea.

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