Study identifies new protection mechanism in breast cancer

Researchers at Karolinska Institutet in Sweden have identified a protein that protects against breast tumour growth and that can be linked to a better prognosis in breast cancer patients. The results, which are published in the journal Nature Communications, may contribute to the development of new therapies for difficult-to-treat forms of breast cancer.

Breast cancer affects about 10 per cent of women during their lifetime and is a major medical and societal burden. Fewer treatment options are available for ER-negative breast cancers, which lack oestrogen receptors (ER) and thus do not respond to hormone therapy. Particularly difficult to treat are so-called triple-negative breast cancers, which lack not only ER but also 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”, says Per Uhlén, professor at the Department of Medical Biochemistry and Biophysics, Karolinska Institutet.

Professor Uhlén and colleagues have identified a novel mechanism by which the ubiquitous protein GIT1 regulates so-called Notch signalling, affecting the initiation and growth of ER-negative breast cancer.

Associated with better prognosis

Studies of tumour cells from breast cancer patients showed that high levels of GIT1 inhibited Notch signalling and protected against tumour growth, while low levels of GIT1 enhanced tumour growth. ER-negative breast tumours from patients had lower levels of GIT1 than ER-positive breast tumours. The results also showed that ER-negative breast cancer patients with high levels of GIT1 have a better prognosis than those with low levels.

Notch signalling 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 signalling in breast cancer patients has previously been linked to a worse prognosis.

“Our results provide important information about a mechanism that controls the initiation and growth of breast tumours,” says Professor Uhlén. “We hope that these findings will inform the development of new therapies for patients with difficult-to-treat breast cancer.”

Collaboration with the clinic

His 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,” says Professor Uhlén. “At Karolinska Institutet, we have state-of-the-art tools and equipment that can push the development of new therapies.”

The research was carried out at Karolinska Institutet with funding from, among others, the Swedish Research Council, the Swedish Cancer Society and the Wallenberg Academy Fellow grant from the Knut and Alice Wallenberg Foundation. The authors declare no competing interests.

Publication: “GIT1 protects against breast cancer growth through negative regulation of Notch.” Songbai Zhang, Ayako Miyakawa, Malin Wickström, Cecilia Dyberg, Lauri Louhivuori, Manuel Varas-Godoy, Kati Kemppainen, Shigeaki Kanatani, Dagmara Kaczynska, Ivar Dehnisch Ellström, Lotta Elfman, Pauliina Kronqvist, Heli Repo, Katsuhiko Mikoshiba, Cecilia Sahlgren, John Inge Johnsen, Per Uhlén. Nature Communications, online 22 March 2022, doi: 10.1038/s41467-022-28631-y.