Small Molecule Inhibitor Turns Breast Cancer Cells More Aggressive

Inhibiting TGF-beta Receptor Type 1 may have a negative impact on breast cancer therapy.

When breast cancer cells were exposed to a TGF-beta Receptor Type 1 (TGFBR1) inhibitor, researchers found that they turned into more aggressive forms of cancer cells.

During the developmental process of breast cancer, tumor cells are able to push past the tissue compartment that confines the mammary gland, invading and spreading to the surrounding tissue. A study published in Oncotarget examined blocking this process by exposing breast cancer cells to the TGFBR1 inhibitor.

By doing this, researchers were able to prevent Twist1, a master gene regulator involved in breast cancer progression, from initiating a cellular program that results in this invasive behavior.

Twist1 constitutes a certain type of protein unsusceptible to therapeutic targeting, therefore researchers sought to inhibit other signaling pathways that Twist1 depended on to stop the invasiveness.

“Initially, using conventional in vitro tissue culture techniques, our results indicated that we were indeed successful, as many of the previously described effects of Twist1-activation were prevented by simultaneously blocking TGFBR1” said first study author Diana Dragoi.

Despite the success, the study took a turn when the breast cancer cells were transferred to a more physiological 3D-environment. Researchers discovered that Twist1 turned the cancer cells invasive, even when TGFBR1 signaling was being blocked.

“Taken together, our study suggests that the inhibition of TGFBR1 does not simply block the ability of master regulator Twist1 to induce invasiveness in breast cancer cells, but redirects the actions of Twist1 to generate breast cancer cells that may be even more aggressive,” said study co-author Anja Krattenmacher.

Breast cancer cells were able to switch into a different mode of invasion, spreading throughout the 3D-environment. The cells also altered to a cohesive strand of cells, as opposed to single cells.

Additionally, the cells were found to have significantly higher rates of proliferation. The results suggested that the cells were better equipped to launch secondary tumors once they disseminated to distant sites, resulting in metastasis.

“These data highlight the importance of diligent preclinical tests that aim to approximate in vivo conditions as much as possible and to test many different parameters,” said study lead Christina Scheel. “This is especially important when aiming to interfere with such a complex, multi-step process as metastasis.”