Breast cancer is the most common cancer in women. One subtype of breast cancer is particularly aggressive: estrogen receptor (ER)-negative basal breast cancer. Researchers of the Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch have now elucidated the key factors for the aggressiveness of this subtype and at the same time have identified targets for the development of new and more effective treatments. The study by Dr. Jane Holland, Regina Vogel, Prof. Walter Birchmeier and other members of the MDC research group, Dr. Balász Györffy (Charité – Universitätsmedizin Berlin and Semmelweis University in Budapest, Hungary) as well as pathologists of the Charité and Dr. Klaus Eckert (EPO Experimental Pharmacology and Oncology GmbH) has now been published online in the open access journal Cell Reports*.
In contrast to estrogen-positive breast cancer, basal breast cancer is not controlled by this female sex hormone. This cancer subtype lacks hormone receptors, which is why in contrast to estrogen-positive or progesterone-positive breast cancer a “hormone withdrawal” (anti-hormone therapy) has no effect. Progesterone is also a female sex hormone. In the latter form of breast cancer, doctors can suppress the cancer growth with anti-hormone therapies, since drugs block the receptors for estrogen or progesterone on the surface of the cancer cells. Furthermore, breast cancer with receptors for the growth factor Her2 (abbreviation for human epidermal growth factor receptor 2) can be targeted with an antibody which occupies the receptors for Her2.
These therapies are not possible with the basal breast cancer subtype, according to Professor Birchmeier and Dr. Holland. In most cases (about 70 percent), the subtype neither has receptors for estrogen nor for progesterone nor Her2; it is therefore “triple negative”. “Thus, the only possible treatment for this cancer is chemotherapy,” they said. “However, because it is so difficult to treat, researchers and clinicians are seeking new ways to more specifically combat this fast-growing and aggressive type of cancer.
An infamous “triple combination”
Researchers have known for some time that two signaling pathways can play an important role in the malignant growth of basal breast cancer. One is the Wnt/beta-catenin signaling pathway, which Professor Walter Birchmeier’s laboratory has been studying for many years. This signaling pathway is essential for embryonic development, cell growth (proliferation) and cell maturation or cell specialization (differentiation). In the clinic it has been shown that patients with a high beta-catenin level may have basal breast cancer.
In addition, a growth factor is involved which researchers have named after its discovery site in the liver: hepatocyte growth factor/scatter factor (HGF/SF). It is referred to as scatter factor because it can separate cells from their respective cluster. It is therefore important for cancer research, as Professor Walter Birchmeier and his staff were able to demonstrate repeatedly: HGF/SF binds to its receptor (Met) in the cancer cell membrane, thus stimulating cancer growth.
Main driver identified for basal breast cancer
Dr. Holland has now shown that an infamous “triple-combination”, Wnt/beta-catenin and HGF/SF, plus an additional factor are to blame for the growth of basal breast cancer. In an adult mouse model, in which both signaling pathways are simultaneously mutated and activated, she identified the first two main drivers that induce the cancer cells to proliferate. Also involved is a system of signaling proteins (chemokines) that is activated by the two signaling pathways Wnt/beta-catenin and HGF/SF. Jane Holland, – she is Australian – already conducted research on this chemokine system during her doctoral thesis at the University of Adelaide. Mice in which additionally the gene for the receptor CXCR4 of this chemokine system has been inactivated are immune to this type of cancer. “Such genetic experiments clearly show that the third component is essential,” Professor Birchmeier said.
In vitro and in vivo in mice, the researchers in Berlin-Buch tested the various inhibitors that have already undergone clinical trials against other cancers but have not been approved. They proceeded step by step, until they ultimately used combinations of the various inhibitors at all three points of attack. Thus, they succeeded in dramatically suppressing cancer growth in mice. Dr. Holland and Professor Birchmeier explained: “A triple attack that blocks both the chemokine system and the two signaling pathways Wnt/beta-catenin and HGF/Met is the most effective.” Dr. Holland added: “This is shown by the fact that after their breast cancer treatment, the mice again formed normal, so-called alveolar structures instead of tumor tissue.” The researchers now hope that their findings will be used in further preclinical trials, and if successful, will also be applied in clinical research.
* Combined Wnt/b-catenin, Met and CXCL12/CXCR4 Signals Characterize Basal Breast Cancer and Predicts Disease Outcome
Jane D. Holland1*, Balázs Győrffy2,3, Regina Vogel1, Klaus Eckert4, Giovanni Valenti1, Liang Fang1, Philipp Lohneis3, Sefer Elezkurtaj3, Ulrike Ziebold11, and Walter Birchmeier
1 Department of Cancer Research, Max Delbrück Center for Molecular Medicine (MDC), Robert-Roessle-Str. 10, Berlin, Germany
2 Research Laboratory of Pediatrics and Nephrology, Hungarian Academy of Sciences – Semmelweis University, Bókay u. 53-54, Budapest, Hungary
3 Institute for Pathology, Charité Medical University, Charitéplatz 1, Berlin, Germany
4 Experimental Pharmacology & Oncology (EPO), Robert-Roessle-Str. 10, Berlin, Germany
Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch
in the Helmholtz Association
Robert-Rössle–Strasse 10; 13125 Berlin, Germany
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