A new study reveals that the metadherin gene (MTDH) plays a role in both cancer metastasis and resistance to chemotherapy. The research, published by Cell Press in the January 6th issue of the journal Cancer Cell, identifies MTDH as a promising therapeutic target for high risk breast cancers.
"Most breast cancer patients resist currently available therapeutic regimens and succumb to recurrent tumors that spread to distant vital organs, such as lung, bone, liver and brain," explains senior study author, Dr. Yibin Kang from the Department of Molecular Biology at Princeton University. "Resistance to chemotherapy and metastasis remain major challenges to curative therapy."
Previous research identified several clinically applicable genetic signatures associated with poor clinical outcomes of breast cancer. However, the signatures differed between independent studies, making it difficult to identify overlapping, functionally relevant genes that might be useful for understanding, and eventually preventing, breast cancer metastasis and chemoresistance.
To further unravel the complex genetic events involved in breast cancer, Dr. Kang and colleagues developed a sophisticated computational algorithm designed to identify genomic changes in an extensive collection of breast tumor samples. The researchers discovered abnormally high copy numbers of chromosomal region 8q22 in more than 30% of breast cancers examined. Patients having this type of breast cancer often had a shorter survival time due to recurrent and metastatic cancers.
The researchers went on to find that among a handful of genes in the 8q22 region, MTDH was responsible for both increased metastasis and increased resistance to chemotherapeutics. MTDH protein increased metastasis of breast cancers to distant organs by enhancing the binding of cancer cells to blood vessels in these organs. In addition, MTDH protein promoted cell survival, allowing cancer cells to become more resistant to a wide variety of chemotherapeutic agents that are currently used to treat breast cancer. Further, when the researchers genetically altered the cancer cells to reduce expression of MTDH, the tumor cells became less capable of metastasis and more likely to be eliminated by chemotherapeutic agents.
"These findings establish MTDH as an important therapeutic target for simultaneously enhancing chemotherapy efficacy and reducing metastasis risk," concludes Dr. Kang. "Molecular targeting of MTDH may not only prevent the seeding of breast cancer cells to the lung and other vital organs but also sensitize tumor cells to chemotherapy, thereby stopping the deadly spread of breast cancer."
The researchers include Guohong Hu, Princeton University, Princeton, NJ; Robert A. Chong, Princeton University, Princeton, NJ; Qifeng Yang, University of Medicine and Dentistry of New Jersey, New Brunswick, NJ; Yong Wei, Princeton University, Princeton, NJ; Mario A. Blanco, Princeton University, Princeton, NJ; Feng Li, Princeton University, Princeton, NJ; Michael Reiss, The Cancer Institute of New Jersey, New Brunswick, NJ; Jessie L.-S. Au, The Ohio State University, Columbus, OH; Bruce G. Haffty, University of Medicine and Dentistry of New Jersey, New Brunswick, NJ; and Yibin Kang, Princeton University, Princeton, NJ, The Cancer Institute of New Jersey, New Brunswick, NJ.