Scientists from the NTU School of Biological Sciences (SBS) have discovered how a protein, Fn14, is behind the aggressive nature of triple negative breast cancer, and how understanding the genetic signalling pathways of this protein can open potential areas for more effective cancer treatment. Their study was published in July 2024 in Nature Communications, which can be viewed here.
From left to right: Kamalakshi Deka, Nicholas Sim, Nanyang Assistant Professor Li Yinghui, Jean-Michel Carter
Triple negative breast cancer
Like most other cancers, breast cancer comes in several types, including the more common invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC). However, 10 to 15 percent of breast cancer cases involve the dreadful-sounding triple negative breast cancer, or TNBC.
TNBC is an aggressive form of breast cancer, one that grows and spreads faster than other types of breast cancer. Its name, triple negative, means that this form of cancer has low levels of three specific molecular biomarkers, which are measurable indicators of biological states or conditions. By observing and measuring biomarkers, scientists can detect or evaluate certain diseases.
In the case of TNBC, the cancer lacks the following biomarkers: the estrogen receptor (ER), the progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER2). Without these biomarkers, hormone therapies that usually target estrogen or progesterone receptors are ineffective, causing an already aggressive form of breast cancer to be even more resistant to treatment and limiting targeted treatment options for patients.
As a result, it is a race for scientists to identify new therapeutic targets for treatment and to improve the outcomes for patients suffering from this particular type of cancer.
The role of Fn14 in TNBC
Fibroblast growth factor-inducible 14 (Fn14) receptor is a protein that exists on the surface of cells. When it is activated by another protein molecule, TWEAK (Tumor Necrosis Factor-like Weak Inducer of Apoptosis), a rather apt acronym, a signalling pathway is triggered in the cell that can cause inflammation, stimulate cell growth and survival, or induce cell death (apoptosis). Fn14 and TWEAK play an important role in injury response and are usually found in low amounts in healthy cells. When you suffer an injury, whether chemical or mechanical in nature, the levels of Fn14 and TWEAK increase in order to trigger cells to repair or die off where necessary, allowing your tissues to repair and for you to recover.
However, under certain disease conditions, like chronic inflammation or cancers, Fn14 and TWEAK are produced at levels that are much too high. This causes diseases to continue developing and spreading in the body.
Prof Yinghui presenting the team’s research during the European Molecular Biology Organization (EMBO) workshop held at the National University of Singapore in April 2024.
New areas for TNBC treatment
Earlier studies have shown that there are high levels of Fn14 present in cases of ER-negative breast cancers. However, in their recently published paper in Nature Communications, a team of scientists from NTU SBS, led by Nanyang Assistant Professor Li Yinghui, have found that Fn14 exists in particularly higher amounts in TNBC patients, which has led to significantly poorer survival rates.
The team found that Fn14 in TNBC patients rewires the genetic makeup of TNBC cells, causing tumours to grow and spread faster. Fn14 does this by activating specific non-coding genetic elements of the TNBC cells, creating regions of “super-enhancers (SE)” that strongly increase gene activity. These SE regions can then activate oncogenes, which are genes that can cause normal cells to become cancerous once overproduced, via chromatin looping. It is these SE regions, and the subsequent oncogenes that they interact with, that the TNBC cells depend on to grow and survive.
This process can result in the creation of a problematic, dysregulated SE-oncogene loop: when the activated SE causes the abnormal expression of oncogenes, the oncogenes can make the TNBC more aggressive in nature and lead to poorer outcomes for the patient.
One such dysregulated SE-oncogene loop results in the activation of the enzyme Nicotinamide phosphoribosyltransferase (NAMPT), which in turn produces the molecule nicotinamide adenine dinucleotide, or NAD+. This molecule helps in cellular energy production as well as the promotion of cell health. This is great in normal healthy cells, but terrible when it comes to cancer cells, which now have increased amounts of energy to form filopodia, which are finger-like structures that extend from the surface of cells and help in metastasis.
By understanding how Fn14 plays a role in the aggressive nature of TNBC cells and the genetic pathways that are associated with the protein, the team’s discovery has opened new avenues and potential molecular targets for scientists to develop TNBC treatments. Future studies could delve into treatments that affect the levels of Fn14 or even target the super-enhancers in TNBC patients, depriving cancer cells of NAD+ that is crucial to their energy production.
To explore more of Prof Yinghui’s research, you can read an earlier post here on her studies on large B-cell lymphoma (DLBCL) protein pathways and the new avenues that have opened on developing targeted cancer treatments.
