Protein abundant in human tumors confers resistance to anticancer drugs

Scientists report that a protein made in excess in the majority of human tumors plays a significant role in the ability of cancer cells to resist traditional treatments. The research study, published in the February issue of Cancer Cell, provides new insight into the biology of cancer cells and may have a significant impact in the design of future, more effective cancer treatments.

Tumor formation results when cells divide in an unregulated fashion and many chemotherapeutic agents are thought to work by inducing apoptosis, a complex process of cell death, to halt proliferation of malignant cells. It is known that most cancer cells do not undergo apoptosis under many stress conditions that would trigger apoptosis in healthy cells, including chemotherapeutic treatments. However, the details of the biology underlying drug action and why some cancers are drug resistant are not well understood. A research team led by Dr. Donald Kufe from the Dana-Farber Cancer Institute in Boston, Massachusetts examined the role of a protein called MUC1 in drug resistance in cancer cells. The level of MUC1 is substantially elevated in most human tumors. Normal levels of MUC1 are thought to play a role in cell repair after damage, inhibiting cell death and promoting generation of new cells. The researchers found that high levels of MUC1 protein, as is found in cancer, reduces traditional apoptosis signals, blocks the apoptotic response to toxic anticancer agents and confers resistance to treatment in animal tumor models. Further, reduction of MUC1 in lung and breast cancer cells is associated with increased sensitivity of these cells to anticancer drugs.

The researchers conclude that abnormal overabundance of MUC1 in human tumors promotes cancer cell survival, even in the presence of agents that normally induce cancer cell death. “We believe that our findings will lead to a better fundamental understanding of cancer biology and treatment. We have uncovered a mechanism in which what appears to be a normal physiological mechanism to protect healthy cells against apoptosis during stress-induced repair could be exploited by human tumors to survive under adverse conditions. In addition, because MUC1 reduces the normal apoptotic response to DNA damaging agents, it is an attractive target for design of future cancer therapeutics,” explains Dr. Kufe.

Jian Ren, Naoki Agata, Dongshu Chen, Yongqing Li, Wei-hsuan Yu, Lei Huang, Deepak Raina, Wen Chen, Surender Kharbanda, and Donald Kufe: “Human MUC1 carcinoma-associated protein confers resistance to genotoxic anticancer agents”

Published in Cancer Cell, February 2004, Volume 5, Number 2, pages 163-176.