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January 11, 2007

A New Target for the Treatment of Breast Cancer:
Berkeley Scientists Find A Potential New Way for Stopping Tumor Proliferation

BERKELEY, CA — The active ingredient in a drug currently being tested to treat rheumatoid arthritis might also one day serve as an effective means of treating one of the deadliest forms of breast cancer. Researchers with the U.S. Department of Energy’s Lawrence Berkeley National Laboratory (Berkeley Lab) 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

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Inhibition of TACE activity reverted the malignant phenotype of tumorous breast cancer cells by blocking the EGFR signaling pathway, a key factor in the control of cell division. In (A) T4-2 breast cancer cells grown in culture formed continuously proliferating, disorganized, apolar colonies. In (B) T4-2 cells treated with an EGFR inhibitor underwent morphological reversion, forming small, smooth, spherical, growth-arrested colonies. In (C) T4-2 cells treated with a broad-spectrum TACE inhibitor underwent morphological reversion similar to that of the EGFR inhibitor–treated cells. (D) shows an absence of tissue polarity in untreated T4-2 cells and (E) shows a restoration of tissue polarity after the cells were treated with the TACE inhibitor.

“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, a post-doctoral cell biologist with the research group of 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.”

Kenny is the co-author along with Bissell of a paper published in the Journal of Clinical Investigation entitled: Targeting TACE-Dependent EGFR-ligand Shedding in Breast Cancer.  This paper presents the latest experimental results from an on-going investigation led by Bissell into the ecology of tumors.

It has long been Bissell’s contention that “no tumor is an island.”  Tumor cells, she maintains, exist in the same microenvironment as healthy cells and must therefore appropriate normal physiological processes to facilitate their growth and spread.  As she and her colleagues have repeatedly demonstrated, this idea can open up potential new avenues and targets for diagnostic and therapeutic applications.

For this latest paper, Kenny and Bissell 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.

“Because of this, we turned our attention to the processes that regulate the production of the ligands which bind and activate EGFR,” Kenny said.  “We reasoned that this binding and activation is essential for EGFR activation and that finding a way to block this interaction might prove to be an important additional approach to explore for inhibition of this pathway.”

spacer image Paraic Kenny
  Paraic Kenny, a post-doctoral cell biologist with the research group of Mina Bissell in Berkeley Lab’s Life Sciences Division, co-authored a paper that describes the potential of the TACE protease for treating one of the deadliest forms of breast cancer.

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.

“We have designed an entirely new way of targeting EGFR signaling in breast cancer,” said Kenny. “Almost all the work to date has involved the use of antibodies that stick to kinases or drugs that block kinase activities.”

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.

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Mina Bissell, a leading authority on breast cancer, has long maintained that tumor cells exist in the same microenvironment as healthy cells and must therefore appropriate normal physiological processes to facilitate their growth and spread.

“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.”

This research was supported by grants and a Distinguished Fellowship Award from the U.S. Department of Energy’s Office of Biological and Environmental Research, the National Cancer Institute,and an Innovator award from the U.S. Department of Defense’s Breast Cancer Research Program to Bissell, and by a Susan G. Komen Breast Cancer Foundation fellowship to Kenny.

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