Navigation Links
Protein protects against breast cancer recurrence in animal model
Date:6/13/2013

PHILADELPHIA - According to the American Cancer Society, nearly 40,000 women in the United States will succumb to breast cancer this year. Most of these women will die not from the primary tumor but rather tumor recurrence the reappearance of the disease following treatment.

Precisely what causes breast cancer recurrence has been poorly understood. But now a piece of the puzzle has fallen into place: Researchers at the Perelman School of Medicine, University of Pennsylvania have identified a key molecular player in recurrent breast cancer a finding that suggests potential new therapeutic strategies.

The study, performed in the laboratory of Lewis A. Chodosh MD, PhD, chair of Cancer Biology and director of Cancer Genetics at the Abramson Family Cancer Research Institute, implicates the tumor suppressor protein Par-4 in recurrent breast cancer.

Par-4 is downregulated in recurrent tumors, and knocking the gene's expression down accelerates tumor recurrence in a mouse model of recurrent breast cancer. Conversely, overexpressing Par-4 delays the onset of tumor recurrence.

Data from human breast cancer patients confirm these findings. The authors analyzed patient tumors from the I-SPY 1 TRIAL, a clinical trial that measured tumor gene expression patterns and response to neoadjuvant chemotherapy. They found that Par-4 expression is low in "residual disease" (that portion of a tumor that survives chemotherapy) compared to the primary tumor prior to treatment, and that women with low Par-4 levels in their primary tumors tend to respond less well to treatment and are more likely to experience a relapse.

The findings appear in this week's issue of Cancer Cell.

The study was led by Chodosh senior postdoctoral fellow, James V. Alvarez, PhD. Alvarez and his colleagues teased apart the role of Par-4 using a mouse model of recurrent breast cancer. In this model, turning "on" the HER2/neu oncogene in mice -- which is turned on in about 20% of human breast cancers -- induces the formation of a primary mammary tumor. Subsequently, turning HER2/neu "off" in a tumor that has arisen causes it to essentially disappear, mimicking the treatment of primary human breast cancers with the anti-HER2/neu agent, Herceptin. But, as in many human patients, at some point in the weeks and months following tumor regression, tumors often return, both in the breast as well as in secondary sites such as the lungs.

By studying these paired primary and recurrent tumors, Alvarez, Chodosh, and their colleagues found that Par-4 expression was dialed down in recurrent tumors relative to primary tumors. When they examined gene expression data from human breast cancer specimens, they found that low Par-4 expression was associated with an increased risk of recurrence and a poorer response to neoadjuvant therapy -- chemotherapy prior to surgery. A poor response to neoadjuvant therapy is associated with an increased likelihood of recurrence.

Based on these findings, the team hypothesized that cells that downregulate Par-4 may be more adept at surviving chemotherapeutic treatment of the primary tumor, and that's precisely what they found. When they compared cells expressing normal levels of Par-4 with cells that had downregulated the gene, they found that it is the cells with low Par-4 levels that persist following treatment. Consequently, it is these cells that are available to give rise to recurrent tumors in the future.

The team then asked what Par-4 actually does to prevent breast cancer recurrence. They found in their mouse models that when HER2/neu is turned off and primary tumors shrink, Par-4 expression ramps up. This causes a defect in cell division, producing cells with more than one nucleus. This, in turn, leads to cell death. Cells that have downregulated Par-4 fail are able to escape this multinucleation process, allowing them to survive therapy and, eventually, give rise to a recurrent tumor.

The bottom line, Alvarez says, is that Par-4 downregulation is both a necessary and sufficient step for breast tumor recurrence. "Par-4 downregulation allows tumor cells to survive tumor regression caused by oncogene inhibition or chemotherapy."

That conclusion suggests that strategies that increase Par-4 expression in tumors could pay therapeutic dividends. In fact, turning Par-4 back on in recurrent tumor cells led to their rapid death. However, "drugging' Par-4 won't be easy", he says.

Par-4 is a tumor suppressor protein that functions through interactions with other proteins. Neither an enzyme nor a signaling receptor, it is not a traditionally "druggable" molecule. However, if researchers can identify the biochemical pathway that controls Par-4, or molecules that can modulate Par-4 activity directly, they may be able to increase the efficacy of neoadjuvant therapy of primary tumors as well as treat recurrent breast cancers more effectively, Alvarez says. The team is now working on identifying pathways that regulate Par-4 levels.


'/>"/>

Contact: Karen Kreeger
karen.kreeger@uphs.upenn.edu
215-349-5658
University of Pennsylvania School of Medicine
Source:Eurekalert

Related medicine news :

1. Warwick scientists uncover how checkpoint proteins bind chromosomes
2. Specific protein triggers changes in neurons in brain reward center linked to cocaine addiction
3. Unusual protein helps regulate key cell communication pathway
4. Protein prevents DNA damage in the developing brain and might serve as a tumor suppressor
5. RANK protein promotes the initiation, progression and metastasis of human breast cancer
6. Protein may represent a switch to turn off B cell lymphoma
7. Protein RAL associated with aggressive characteristics in prostate, bladder and skin cancers
8. Breast cancer clinical trial tests combo of heat shock protein inhibitor and hormonal therapy
9. Pivotal role for proteins -- from helping turn carbs into energy to causing devastating disease
10. New molecular structure offers first picture of a protein family vital to human health
11. Wayne State University researcher examines proteins role in diabetic retinopathy
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:1/18/2017)... ... January 18, 2017 , ... A recent video posting of a new fidget ... benefits of fidgeting to relieve stress and anxiety. No one was more surprised ... Pen had just completed a successful Kickstarter campaign raising $67,000 on the popular crowdfunding ...
(Date:1/18/2017)... Baltimore, MD (PRWEB) , ... January 18, 2017 ... ... University of Maryland Fischell Department of Bioengineering are collaborating on a research project ... professor in bioengineering, the project seeks to use nanotechnology to control the disease ...
(Date:1/18/2017)... ... January 18, 2017 , ... A Palm Beach doctor plans to run ... international charity that provides free surgery to poor children suffering from cleft lip and ... I have run to support the efforts of the American Heart Association and the ...
(Date:1/18/2017)... , ... January 18, 2017 , ... At Hallmark Nameplate, ... announce that they have achieved certification to ISO 13485. This certification is another way ... up to date products and services that they need. , The ISO 13485 Certification ...
(Date:1/18/2017)... ... January 18, 2017 , ... The Hear the World Foundation, ... the donation of cochlear implants. In February 2017, the first three children with ... chance of leading an independent life. This engagement builds on the support the ...
Breaking Medicine News(10 mins):
(Date:1/18/2017)... , Jan. 18, 2017 The Philadelphia Pediatric Medical ... developing medical devices for children. The Consortium chose ... seed grants of $50,000 each. The devices under ... nerve signals, a hand-operated rapid blood delivery system for emergency ... babies. ...
(Date:1/18/2017)... Jan. 18, 2017  Kratom leaves, from a ... are often used to prepare tea-like beverages and ... million Americans annually to increase alertness, enhance well-being ... for minor aches and pains. PinneyAssociates, review of ... to assist FDA and DEA in determining the ...
(Date:1/18/2017)... de 2017  Hoy, en el Foro Económico Mundial, ... global para avanzar el acceso a la prevención de ... renta baja y baja-media (LICs y LMICs). ... particularmente en países de renta baja y media, donde ... muertes relacionadas con NCD. El objetivo de Access Accelerated, ...
Breaking Medicine Technology: