Protein allows cells altered by the oncoprotein ErbB2/HER2 to escape their bonds
Active, but non-invasive breast cancer is set free to roam as invasive breast cancer when an overexpressed protein converts it to a different cell type, scientists at The University of Texas M. D. Anderson Cancer Center report in the Sept. 9 issue of the journal Cancer Cell.
"We have discovered a key molecular mechanism for the deadly transition of non-invasive breast cancer into invasive disease," said senior author Dihua Yu, M.D., Ph.D., professor in M. D. Anderson's Department of Molecular and Cellular Oncology.
Overexpression of the protein 14-3-3ζ (zeta) launches a molecular cascade that removes bonds that tie the premalignant cells together and hold them in place, converting them from stationary epithelial cells to highly mobile mesenchymal-like cells, Yu and colleagues report. This epithelial-to-mesenchymal transition (EMT) is recognized as a crucial step in metastasis, the spread of cancer to distant organs that causes 90 percent of all cancer deaths.
The researchers show that 14-3-3ζ teams with the oncoprotein ErbB2, also known as HER2, in a two-hit process to convert normal mammary cells to invasive cancer cells.
In addition to identifying this key step in EMT, Yu notes the findings also provide:
- A biomarker in 14-3-3ζ to identify high-risk patients for more aggressive treatment before their noninvasive breast cancer converts to invasive disease.
- New therapeutic targets among the components of the molecular pathway launched by 14-3-3ζ. Some drugs already aim at these targets, Yu said.
- A solution to a puzzling mystery about how a subset of non-invasive breast cancer with excessive presence of a ErbB2/HER2 develops into invasive breast cancer.
Yu and colleagues previously showed that 14-3-3ζ is overexpressed in many other cancer types, like lung, liver, uterine, stomach cancers. "Our findings might have broader implications relating to the mechanism of invasion and metastasis in other types of cancer," Yu said.
Unzipping cancer cells
The team set out to address a longstanding puzzle, Yu said. ErbB2, an oncoprotein that promotes metastasis, is overexpressed in 50 to 60 percent of the noninvasive breast cancer known as ductal carcinoma in situ (DCIS). However, that same protein is overexpressed in only about 25 percent of invasive breast cancers, which seemed counterintuitive.
In a series of lab experiments, Yu and colleagues showed that overexpression of ErbB2 accompanied by overexpression of 14-3-3ζ can change DCIS into invasive breast cancer. This only occurs in about half of ErbB2-overexpressing DCIS, the team found, explaining the numerical puzzle.
Overexpression of ErbB2 converts normal breast duct cells into abnormal cells that reproduce quickly, are capable of moving, and resist programmed cell death that usually kills aberrant cells. What prevents these DCIS cells from becoming invasive, Yu said, is that they are locked together in zipper-like fashion by the cell surface protein E-cadherin, a trait known as cell-cell adhesion.