Scientists in the US looking for genomic changes in breast tumor samples found that a gene called metadherin (MTDH) appears to play a dual role in both helping cancer spread (metastasis) and maintain resistance to chemotherapy. They said this research identifies MTDH as an important new target for the treatment of high risk breast cancers.
The discovery was made by senior investigator Dr Yibin Kang from the Department of Molecular Biology at Princeton University, in New Jersey, and colleagues, and is written up in a paper in the 6 January issue of the journal Cancer Cell.
As Kang explained:
“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.”
“Resistance to chemotherapy and metastasis remain major challenges to curative therapy,” added Kang.
Previous studies have found several genetic signatures linked to breast cancers with poor prognoses, but none has yet shown whether these different signatures had any common genetic components.
To do this, the researchers developed and used a computer-based algorithm to map the minimum number of genetic signatures linked to breast cancers that had a poor prognosis in an extensive collection of tumor samples.
They found that a particular genetic pattern on chromosome region 8q22 occurred in more than 30 per cent of the poor prognosis tumors whose patients had shorter survival times because of recurrent and metastatic cancers. They also found that MDTH was among a small number of genes within this region: this gene is overexpressed in more than 40 per cent of breast cancers and is linked to poor clinical outcomes, so they investigated it further.
By doing what they called a “functional characterization”, Kang and colleagues established that MTDH had a dual role: it promoted the “seeding” of new cancer sites (metastasis), and it enhanced tumor resistance to chemotherapy.
To seed new cancer sites, the MTDH protein encouraged cancer cells to bind to the blood vessels of the organs at the new sites. And to enhance chemoresistance, it promoted cancer cell survival against a range of chemotherapy agents that are used to treat breast cancer.
Also, when the researchers reduced MTDH expression in the cancer cells they found they were less able to promote metastasis and chemoresistance.
Kang and colleagues concluded that:
“These findings establish MTDH as an important therapeutic target for simultaneously enhancing chemotherapy efficacy and reducing metastasis risk.”
“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,” they added.
“MTDH Activation by 8q22 Genomic Gain Promotes Chemoresistance and Metastasis of Poor-Prognosis Breast Cancer.”
Guohong Hu, Robert A. Chong, Qifeng Yang, Yong Wei, Mario A. Blanco, Feng Li, Michael Reiss, Jessie L.-S. Au, Bruce G. Haffty, Yibin Kang.
Cancer Cell, Volume 15, Issue 1, 9-20, 6 January 2009
doi:10.1016/j.ccr.2008.11.013
Sources: Journal article, Cell Press.
Written by: Catharine Paddock, PhD