Navigation Links
Overexpressed protein converts noninvasive breast cancer into invasive disease

HOUSTON ― 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.

"Overexpression of 14-3-3ζ is the catalyst for a molecular pathway that strips E-cadherin from the cells, setting the cells loose from each other," Yu said. These cells also change in appearance from blunt normal breast duct cells to a narrow spindle shape characteristic of a mesenchymal-like cell.

Double overexpression reduces survival time

Epithelial cells line an organ or its cavities and are generally immobile. Mesenchymal cells are mobile and can differentiate into many different cell types, for example, to repair injury. Epithelial-mesenchymal transition is known to repress E-cadherin, decrease cell-cell adhesion and increase a cell's capacity to move. An estimated 80 percent of all solid tumors are carcinomas, cancers of the epithelial tissue.

Mice injected with a breast cancer cell line with both proteins overexpressed had three times the metastasis as mice with a control cancer cell line.

The researchers examined 107 invasive breast cancer cases and found that 23 of the cancers overexpressed both proteins. Those patients also had significantly shorter survival times due to metastasis-related deaths than those whose tumors expressed one or neither of the proteins.

Overexpressed 14-3-3ζ, the team showed, interacts with and stabilizes the receptor protein TβR1, which activates smad2/3 and moves them into the cell nucleus, where they in turn increase expression of ZFHX1B, which then represses expression of the adhesion protein E-cadherin.

Yu said that it will be very challenging to target 14-3-3ζ by drugs because it also regulates other important proteins in normal cellular processes. The downstream components such as TβR1 can be targeted with drugs that are under clinical trials.


Contact: Scott Merville
University of Texas M. D. Anderson Cancer Center

Related medicine news :

1. A new Eph receptor tyrosine kinase overexpressed in gastric cancer was found
2. U of T researchers identify protein
3. Inhibition of NF-kappa B, a key inflammatory protein, reduced radiation toxicity in zebrafish
4. Key Protein May Link Obesity, Diabetes, Heart Woes
5. Cell Biosciences Launches Unique Protein Phosphorylation Assay Service
6. Researchers identify protein involved in causing gum disease, osteoporosis, arthritis
7. Researchers identify new, cancer-causing role for protein
8. Protein May Identify Deadlier Breast Cancer
9. Naked(R) Juice Brings Power to the People With Two New Protein Zone Flavors: Mango and Double Berry
10. Pitt scientists find intrinsic changes in protein shape influence drug binding
11. Plasma protein Therapies Association Focuses Attention on Donors and Facilities
Post Your Comments:
(Date:11/25/2015)... ... November 25, 2015 , ... ... sauna parts and accessories. , Sauna accessories help improve the bather experience in ... personality. From basic styles for the purist looking for simplicity in design to ...
(Date:11/25/2015)... ... 26, 2015 , ... Ministers, senior government and UN agencies, ... Centres of Excellence, and public R&D institutions, civil societies and other partners gathered ... 5th African Network for Drugs and Diagnostics Innovation, ANDI, Stakeholders Meeting. The three- ...
(Date:11/25/2015)... ... November 25, 2015 , ... For the first time, ... Two Organizations, One Beat ” campaign. The partnership between the two groups began in ... in MAP International’s cause. , MAP International was founded in 1954 and is an ...
(Date:11/25/2015)... FL (PRWEB) , ... November 25, 2015 , ... ... center, is encouraging people across the country to celebrate their sobriety and show ... people to post “before and after” photos this Thanksgiving with the hashtag #FacesOfGratitude ...
(Date:11/25/2015)... (PRWEB) , ... November 25, 2015 , ... On November ... training center for the Narconon network, announced the release of a new cutting edge ... the Narconon organization has been working with drug- and alcohol-addicted individuals with the purpose ...
Breaking Medicine News(10 mins):
(Date:11/26/2015)... , 26 november 2015 ... kondigt de geplande investering aan van ten ... de laboratoria en het mondiale hoofdkantoor in ... uitbreiding zal resulteren in extra kantoorruimte en ... aan de groeiende behoeften van de farmaceutische ...
(Date:11/26/2015)... UTRECHT , Nederland, November 26, 2015 ... --> Een nieuwe aanpak combineert ... van gevorderde kanker. ... -->      (Photo: ... van het Leids Universitair Medisch Centrum (LUMC) ...
(Date:11/26/2015)... 26, 2015 Research and Markets ( ) ... Pacemaker Market Outlook to 2019 - Rise in Cardiac Disorders ... report to their offering. Boston ... Boston scientific and others. --> ... Biotronik, Boston scientific and others. ...
Breaking Medicine Technology: