Investigational Agent May Promote Metastasis in Triple-Negative Breast Cancer

A new study shows that in some cases, inhibiting the growth of primary tumors can promote the spread of tumor cells to other parts of the body. Dr. Hoa H. Truong and Dr. Erik H. J. Danen, of the Leiden Academic Centre for Drug Research at Leiden University in the Netherlands, and colleagues show that agents being tested to treat breast cancer may actually promote metastasis. The study was published in Science Signaling.

Drugs that target integrins containing the β1 subunit have been shown to inhibit tumor growth, sensitizing cells to radiation and cytotoxic chemotherapy in preclinical breast cancer models. The agents are in clinical development.

Integrins are protein receptors, providing communication between cells and their environment. They link the extracellular matrix (ECM) to cells, regulating processes such as cell motility, migration, and proliferation. Integrins transduce signals from both cells to the ECM and vice versa.

In vitro tests using E-cadherin–positive triple-negative breast cancer (TNBC) cell lines showed that the blocking of the β1 integrin function allows individual cell migration. In culture, TNBC cells treated with integrin inhibitors were able to invade into the surrounding three-dimensional collagen matrix. Instead of a mass cell movement, the researchers saw individual cells that burrowed into the collagen matrix.

E-cadherin is a calcium-regulated cell-to-cell adhesion molecule whose inactivation is a marked change associated with invasive breast cancer.

Using zebra fish embryos as a model, the TNBC cells that were depleted of β1 integrin were able to disseminate throughout the embryo. When implanted into mice, the TNBC cells were more able to form metastases in the lungs, even as the treatment curbed growth of the originally implanted tumors, in comparison with tumors that were implanted by the same TNBC cells but were not depleted of β1 integrin.

Restoring levels of the β1 integrin protein could repair the cohesion of cells in culture and it also prevented lung metastases in mouse models, though it did not affect the growth of the primary tumors.

“This study demonstrates that β1 integrin–mediated cell-ECM interactions support orthotopic breast cancer growth, but that inhibition of β1 integrins can trigger a rewiring of signaling pathways that lead to enhanced metastatic spread in TNBC,” stated the authors in their discussion. “The effect of depletion of the integrins is context-dependent.” Cells that move as single individual cells are not as readily affected by the disruption of integrins and ECM attachments as those that move as a cohesive cell mass that can apparently switch to a promigratory state.

“These findings raise concerns with respect to the use of β1 integrins as drug targets to sensitize tumors to radio- or chemotherapy,” stated the authors. “Although tumor shrinkage is achieved and the growth of metastatic colonies is attenuated, in certain breast cancer types such as E-cadherin–positive triple-negative variants, reprogramming of the surviving cells may aggravate metastatic spread.”