Researchers at Karolinska Institutet in Sweden have identified a protein, GIT1, that protects against the growth of estrogen receptor (ER)-negative breast tumors, and which can be linked to a better prognosis in breast cancer patients. Results from the team’s studies, which suggest that GIT1 activity is involved in the regulation of Notch signaling, could help point to the development of new therapies for hard-to-treat forms of breast cancer.
“Our results provide important information about a mechanism that controls the initiation and growth of breast tumors,” said research lead Per Uhlén, PhD, a professor at the department of medical biochemistry and biophysics, Karolinska Institutet. “We hope that these findings will inform the development of new therapies for patients with difficult-to-treat breast cancer.”
Uhlén and colleagues reported on their findings in Nature Communications, in a paper titled, “GIT1 protects against breast cancer growth through negative regulation of Notch,” in which they concluded, “We identified G protein-coupled receptor kinase-interacting protein 1 (GIT1), an evolutionarily conserved and ubiquitous cytoplasmic adaptor protein involved in multiple cell signaling pathways, as a modulator of Notch signaling in breast cancer and a predictor of poor prognosis in human ER(-) breast cancer … Additionally, GIT1 could serve as a biomarker in ER(-) breast cancer.”
Breast cancer will affect about 10% of women during their lifetime, and represents a major medical and societal burden, the authors noted. The different categories of breast cancer are classified based on the presence or absence of the estrogen receptor, and so are either ER(+) or ER(-) breast cancers. And while hormonal (antiestrogen) therapies are relatively effective for ER(+) tumors, ER(-) breast cancers don’t respond to hormone therapy and so, the team explained, “… fewer treatment options are available for ER(-) breast cancers, particularly for so-called triple-negative breast cancers (TNBCs), which are negative not only for ER but also for the progesterone receptor and HER2 receptor. Identification of new molecular mechanisms that regulate the growth of ER-negative breast cancer is warranted, as these mechanisms may represent novel therapeutic targets.”
The researchers have now identified a novel mechanism by which the ubiquitous protein GIT1 regulates Notch signaling, affecting the initiation and growth of ER(-) breast cancer. Their experiments with tumor cells from breast cancer patients showed that high levels of GIT1 inhibited Notch signaling and protected against tumor growth, while low levels of GIT1 enhanced tumor growth. They also found that ER(-) breast tumors from patients had lower levels of GIT1 than ER(+) breast tumors. Morever, investigators stated, “GIT1 knockdown in ER(-) breast tumor cells increased signalling downstream of Notch and activity of aldehyde dehydrogenase, a predictor of poor clinical outcome … GIT1 interacts with the Notch intracellular domain (ICD) and influences signalling by inhibiting the cytoplasm-to-nucleus transport of the Notch ICD.”
The team’s results also showed that ER(-) breast cancer patients with high levels of GIT1 have a better prognosis than those with low levels. “From a breast cancer diagnostics perspective, it is interesting to note that the GIT1 protein levels were lower in ER(-) than in ER(+) breast cancer and that lower GIT1 levels in ER(-) breast cancer patients correlated with poor relapse-free survival,” they wrote.
Further studies in mice carrying human-derived tumors confirmed that overexpression of GIT1 in ER(-) cells prevented or reduced Notch-driven tumor formation. “Excitingly, GIT1 overexpression substantially reduced tumor formation in these animals,” the authors commented. “… these data indicated that high levels of GIT1 protect against the initiation of tumor growth through attenuation of Notch signaling and that loss of GIT1 leads to accelerated tumor formation via elevated Notch signaling.”
Notch signaling is an evolutionarily conserved cell-cell communication mechanism that has been shown to regulate cell fate decisions in most organs of the body and at different steps during cell development. Overactive Notch signaling in breast cancer patients has previously been linked to a worse prognosis. “… the discovery of the GIT1-Notch axis in ER(-) breast cancer sheds light on the control of Notch signaling and identifies GIT1 as a guardian against breast cancer growth,” the scientists commented.
Uhlén’s research group is actively collaborating with clinicians treating patients with cancer to focus on research topics that are crucial for the treatment of patients. “We want to conduct research that can benefit patients with severe diseases,” said Uhlén. “At Karolinska Institutet, we have state-of-the-art tools and equipment that can push the development of new therapies.”