'Death-associated protein' promotes cancer growth in most aggressive breast cancers
Although traditionally understood to induce death in cancer cells, researchers have discovered that the death-associated protein kinase 1 (DAPK1) is actually essential for growth in breast and other cancers with mutations in the TP53 gene. This discovery indicates DAPK1 may be a promising new therapeutic target for many of the most aggressive cancers. The discovery was published in the Journal of Clinical Investigation (2015; doi:10.1172/JCI70805).
As its name implies, DAPK1 has well studied roles in activating pathways that stimulate apoptosis, or programmed cell death, in cancer cells. However, the current findings, from researchers at The University of Texas MD Anderson Cancer Center in Houston, TX, report that DAPK1 functions much differently in cancers with mutations in the TP53 gene (tumor protein p53).
"This is a little studied kinase that has not been previously focused on for the treatment of cancer," said senior author Powel Brown, MD, PhD, professor and chair of Clinical Cancer Prevention. "We discovered a yin and yang phenomenon in terms of DAPK1 function. In normal cells this protein functions as a death inducer, but in TP53 mutant cells DAPK1 acts a critical driver of cancer cell growth."
DAPK1 was identified while searching for new therapeutic targets in aggressive breast cancers, Dr. Brown explained. Breast cancers are often classified according to the presence or absence of three receptor proteins: estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2).
Those tumors lacking ER (ER-negative), which represent 30% to 40% of all breast cancers, are typically more aggressive, and have a worse prognosis than ER-positive tumors. These also include triple receptor-negative breast cancers (TNBCs), which are particularly aggressive. Unfortunately, there are few effective treatments for these tumors.
The researchers found that DAPK1 was significantly elevated in ER-negative compared to ER-positive breast cancers. Higher levels of a death-associated protein in this aggressive subtype presented a conundrum that prompted further investigation.
Although DAPK1 levels did not appear directly affected by ER, higher expression of DAPK1 did correlate significantly with mutations in TP53, which are abundant in ER-negative breast cancers. This was true especially in TNBCs, 80% or more of which harbor TP53 mutations.
DAPK1 itself appears to be an indicator of poor prognosis. Patients with high levels of DAPK1 had significantly lower survival times compared to those with low levels of DAPK1, particularly in patients with TP53 mutations.
By depleting or inhibiting DAPK1 in breast cancer cell lines and mouse models, the researchers learned that cells with TP53 mutations require DAPK1 for their continued growth. Blocking DAPK1 significantly suppressed growth in TP53-mutant cells, but had no effect in those with normal TP53.
The researchers also showed that these results were mirrored in cells from other cancer types, including lung, ovarian, and pancreatic, which contain mutations in TP53. As TP53 is the most commonly mutated gene across all cancer types (>50%) and is associated with a worse prognosis, DAPK1 may be a promising therapeutic target for a broad group of aggressive tumors.
In the current study, the research team clarified the method by which DAPK1 promotes cancer growth. Their findings revealed that DAPK1 turns on a series of growth-stimulating proteins, collectively known as the mTOR pathway. Although they hypothesize that that loss of TP53 activity shifts DAPK1 activity towards the growth-promoting pathway, this regulation of DAPK1 by TP53 is unclear and is the focus of ongoing investigations.