Researchers have demonstrated that inhibiting the activity of the protease enzyme known as TACE can deprive tumor cells of a key factor needed for their proliferation. TACE is strongly present in a form of breast cancer which responds poorly to current therapies.

" We have shown that inhibition of the TACE protease in breast cancer cells blocks the shedding of two critical growth factor proteins and results in an inhibition of a key signaling pathway that controls cell division," said Paraic Kenny and Mina Bissell, in Berkeley Lab's Life Sciences Division. " Based on analysis of cells grown in three-dimensional cultures, the inhibition of this protease results in the reversion of the malignant phenotype of these breast cancer cells and switches their behavior back to a phenotype very reminiscent of non-malignant breast epithelial cells."

The study is published in the Journal of Clinical Investigation.

Researchers looked into the pathway by which the EGFR signal is carried. EGFR, which stands for Epidermal Growth Factor Receptor, is the protein on the outer surface of a cell that is activated by EGF and related growth factors and signals for the cell to divide. Given that one of the hallmarks of cancer is cell division run amok, the reduction of high levels of EGFR activity has long been a primary target for anti-cancer drug development. So far, however, drugs aimed at directly inhibiting EGFR activity have met with only limited success in the cancer clinic, primarily in a small number of lung cancers.

Earlier studies had indicated that TACE ( Tumor necrosis factor-Alpha-Converting Enzyme ) acts like a molecular scissors that releases from the cell surface a pair of ligands, called Amphiregulin and TGF-alpha, which activate EGFR.

Bissell and Kenny found that by targeting TACE ( also known as ADAM17 ) with either molecular inhibitors or short interfering RNAs ( siRNAs ) that silence the TACE gene, they could effectively block the shedding of Amphiregulin and TGF-alpha ligands. This resulted in the inhibition of EGFR signaling and the reversion of malignant characteristics in tumor cells.

It is the first reported use of protease inhibitors to stop breast cancer cell proliferation and restore the normal breast tissue structure.

These newest results are very much in keeping with Bissell's contention that cancer growth and spread is not solely a tumor cell-autonomous process brought on by a genetic mutation. Bissell is one of the leading proponents of the idea that a cell's genetic information is supplemented by contextual information encoded within the microenvironment that surrounds the cell.

" It is becoming increasingly apparent that, as with other organs, the biogenesis of the tumor represents an interaction between the tumor cell, other types of cells and the rest of the microenvironment," she said.

Kenny and Bissell successfully tested their protease blocking approach on several different breast cancer cell lines. In addition, they examined the data from 295 breast cancer patients and found that tumors which produced the highest levels of TACE and the TGF-alpha ligand posed the greatest risk to women.

" Women with those types of tumors would seem to be poorly served by existing treatments and may stand to benefit from therapies that are based on the inhibition of TACE activity, " said Kenny. " We would like to see some of the companies who have developed the new generation TACE inhibitors for treatment of rheumatoid arthritis also consider evaluating them in cancer patients."

Kenny stressed that the importance of EGFR to so many different tumor types, including lung, head and neck, bladder, colorectal and kidney, makes it likely that " TACE inhibition has the potential to be an effective means of stopping tumor growth for EGFR-dependent cancers outside the breast as well."

Source: DOE/Lawrence Berkeley National Laboratory, 2007

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