Women with triple-negative breast cancer (TNBC) often succumb to the devastating disease with limited therapeutic options.

Now researchers have found that the enzyme MAPK4 seems to play an important role in TNBC.

Scientific evidence confirming the role of the enzyme MAPK4 in cancer growth and resistance to some medicines is rapidly developing.

In a recent study published in the journal Nature Communications, researchers from Baylor College of Medicine and other institutions indicate that MAPK4 appears to have a crucial role in triple-negative breast cancer (TNBC), a deadly illness with limited treatment options.

The researchers identified that a sizable fraction of TNBC expressed considerable amounts of MAPK4 after analyzing available genomic datasets. In animal models, knocking down MAPK4 lowered human TNBC cell growth and made the cells more responsive to medicines that disrupt PI3K, a known cancer-growth-promoting signaling pathway.

“In this work, we have combined two long-term interests of my lab: studying the role MAPK4 plays in human cancers and better understanding breast cancer, the most commonly diagnosed cancer worldwide,” says corresponding author Dr. Feng Yang. “In particular, this study focused on TNBC, the subtype of breast cancer that is the hardest to treat.”

The researchers initially examined the gene expression profiles of 817 human breast tumors from the Cancer Genome Atlas dataset, which included a wide range of breast cancer subtypes. They discovered that MAPK4 expression is higher in 30% or more of basal-like breast cancer subtypes, 70 to 80% of which are TNBC.

The researchers also looked at MAPK4 expression in a collection of breast cancer patient-derived xenografts (PDX) from Baylor’s cancer center, the majority of which are TNBC. PDX is a term that refers to a sort of animal model of human cancer that is extremely accurate in simulating the human state. Yang and colleagues also discovered elevated MAPK4 expression in a large subset of TNBC PDX tumors.

“Previous work from our lab had shown that MAPK4 can play a cancer-promoting role in other cancer types, such as prostate cancer,” Yang adds. “Finding that the levels of MAPK4 are elevated in a significant subset of TNBC prompted us to investigate whether MAPK4 could also contribute to TNBC.”

The scientists modified MAPK4 gene expression levels in seven different human TNBC cell lines, some of which expressed higher levels of MAPK4 than others. After removing MAPK4 by either knocking it down or knocking it out, the growth of the cells was significantly cut down, which suggests that MAPK4 is a part of TNBC. The researchers also raised MAPK4 levels in low-expressing TNBC, which helped the cells grow. These data all point to MAPK4 playing a role in TNBC development.

The mechanism behind MAPK4’s cancer-promoting involvement in TNBC was then investigated further by Yang and his colleagues.

“We had previously found that MAPK4 promotes growth in other cancer types by activating in cells a cancer-promoting signaling pathway called AKT,” Yang adds. “Here we showed that this is also the case in TNBC.”

TNBC can activate AKT by two different methods, one of which is mediated by MAPK4 and the other by a different enzyme called PI3K, as previously mentioned.

“We knew that alterations in the PI3K pathway were common in TNBC, but yet the therapeutic benefits of PI3K inhibitors were limited,” according to the author. “Here we provide a mechanism that can explain the inhibitors lack of efficacy.”

The researchers hypothesized that suppressing PI3K would allow cells to activate AKT via MAPK4 and hence continue to develop.

The researchers observed that cutting down MAPK4 made the cells more sensitive to PI3K inhibitors and reduced cancer growth. Overexpressing MAPK4 in low-expressing TNBC made the cells more resistant to PI3K inhibitors and allowed them to continue to grow.

“Altogether, our findings suggest a new therapeutic opportunity for TNBC based on MAPK4 expression, perhaps including a combination of inhibitors to help control cancer growth,” the author said. “Future studies will help clarify this idea.”

Source: 10.1038/s41467-021-27921-1

Image Credit: Getty

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