Researchers of the Max Delbrück Center (MDC) in 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, Professor Walter Birchmeier, Dr. Balász Györffy (Charité Berlin, Semmelweis University in Budapest, Hungary) as well as 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”
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.
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/-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 Ziebold1, and Walter Birchmeier11 Department of Cancer Research, Max Delbrück Center for Molecular Medicine (MDC), Robert-Roessle-Str. 10, Berlin, Germany
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