Triple-negative breast cancer (TNBC) is one of the most aggressive and difficult-to-treat forms of breast cancer. Unlike other breast cancer subtypes, TNBC lacks the three key receptors — estrogen, progesterone and HER2 — that most targeted therapies rely on. This means that patients diagnosed with TNBC have fewer treatment options and face a higher risk of metastasis, where cancer spreads to other parts of the body. Alarmingly, the five-year survival rate drops from over 90% when TNBC is localized to just 11.5% once it becomes metastatic. New treatments are urgently needed.
In a major breakthrough, researchers in the lab of Associate Professor Olga Razorenova at the UC Irvine Charlie Dunlop School of Biological Sciences have uncovered a promising new path forward. Their study, recently published in the British Journal of Cancer, identifies a cellular pathway that plays a critical role in helping TNBC cells to metastasize. Most notably, the research points to an already-druggable target that could one day halt the disease’s deadly progression.
“For a very long time it has been accepted that cancer cells rely on glycolysis for energy production,” explains Professor Razorenova, referencing a process known as the Warburg effect. “But recent research has concluded that glycolysis needs to be paired with oxidative phosphorylation (OXPHOS) for tumor cell survival.” What makes this pairing especially concerning is that OXPHOS has now been shown to drive both metastasis and resistance to treatment in various cancers, including TNBC.
Razorenova’s lab zeroed in on a specific protein, CDCP1, that is overactive in TNBC and known to promote metastasis. In their new study, the researchers revealed that CDCP1 activates another protein called Src — specifically a version of Src that operates inside mitochondria. This mitochondrial Src then ramps up OXPHOS, leading to effective TNBC cell migration and metastatic spread throughout the body.
Assistant project scientist and the paper’s first author Jordan Woytash, who played a central role in the project, described one of the major technical hurdles they had to overcome. “Quantitating Src localization to mitochondria was a challenge, mainly imposed by the resolution of the methods available to us,” Woytash explains. “We had to develop 3D imaging protocols to assign Src localization to mitochondria and quantitate it — reporting for the first time that 20% of total cellular Src is involved in signaling inside mitochondria in TNBC.” This advancement allowed the team to confirm the mitochondrial role of Src and its relationship with CDCP1.
The team’s most exciting finding was that by inhibiting this CDCP1/Src pathway, they could significantly reduce the cancer cells’ energy production, as well as production of an important signaling molecule in mitochondria (NAD+), stimulating cancer cell migration and metastasis. Even more encouraging: pharmaceutical inhibitors of this pathway already exist. “We are excited as this very pathway has already developed therapeutics and novel therapeutics are currently being tested,” says Razorenova. “Inhibitors of the CDCP1/Src pathway can be adapted to TNBC therapeutic regimens, especially when used in combination with standard-of-care chemotherapy to combat therapeutic resistance.”
The implications are far-reaching. Not only could this discovery lead to more effective treatments for TNBC, but it also opens the door to more personalized therapies. By better understanding how mitochondrial Src functions, researchers can begin to develop biomarkers to identify which patients are most likely to benefit from these new interventions. As Razorenova puts it, “We need to better understand Src signaling in mitochondria to develop biomarkers of its activity in TNBC. This information is important to stratify patients and achieve durable therapeutic responses.”
This research also serves as a powerful example of how basic science can directly impact patient outcomes. Without deep investigations into how cancer cells balance glycolysis and OXPHOS, these insights, and their therapeutic potential, would remain hidden. Through funded research like this, we edge closer to turning the tide against diseases like TNBC. By unlocking new molecular mechanisms, scientists can bring hope to patients who currently have few options.