Navigation Links
Breast stem-cell research: Receptor teamwork is required and a new pathway may be involved
Date:5/30/2012

MADISON Breast-cancer researchers at the University of Wisconsin-Madison have found that two related receptors in a robust signaling pathway must work together as a team to maintain normal activity in mammary stem cells.

Mammary stem cells produce various kinds of breast cell types. They may also drive the development and growth of malignant breast tumors.

Published recently in the Journal of Biological Chemistry, the research also suggests that a new signaling pathway may be involved, a development that eventually could take cancer-drug manufacturers in a new direction.

"We wanted to know if we could use this knowledge to inform us about what might be the transition that occurs to start tumor growth and maintain it," says senior author Dr. Caroline Alexander, professor of oncology at the McArdle Laboratory for Cancer Research at the School of Medicine and Public Health.

The paper describes new information about the Wnt signaling pathway. Wnt signaling underlies numerous activities in normal development, but when the system is unregulated, cancer often occurs.

"Wnt signaling is very important for both stem cells and tumor growth. We need to know the details of the signaling process so that we can use the positive aspects of Wnt signaling for regenerative medicine, and eliminate the negative cancer-causing aspects," says Alexander, a member of the UW Carbone Cancer Center (CCC).

Regenerative biologists typically add Wnt proteins together with other agents to guide the differentiation of lung, bone and heart stem cells, she notes.

The UW researchers zeroed in on two related Wnt receptors on the cell surface--LRP5 and LRP6. The receptors normally respond to Wnt ligands that approach cells to initiate a signaling cascade inside.

Scientists have known that when some abnormality causes over-expression of Wnt signaling, many types of cancer can arise. They think that the over-expression of the LRP6 receptor may be important to some of the worst-outcome triple-negative breast tumors. On the other hand, LRP5 is clearly necessary for mammary stem cells to work.

Wnt ligands typically attach at the cell surface to a multi-component receptor complex that includes an LRP or to another receptor called Frizzled. Binding with specific receptors ultimately leads several different types of signal to travel down specific arms of the pathway to activate Wnt-target genes located in the nucleus.

In earlier research, Alexander and her team found that LRP5 and LRP6 serve different functions in the mouse mammary gland. The current research examined the signaling potential of each receptor.

"Our hypothesis was that different Wnt ligands activate the Wnt pathway by preferentially signaling through either LRP5 or LRP6," Alexander says.

To test the hypothesis, researchers treated embryonic mouse cells with different physiologically relevant Wnt ligands. They found that both LRP5 and LRP6 were required to respond optimally to one group of Wnt ligands.

Over-expression of either LRP5 or LRP6 overcame the need for both receptors to be present, suggesting that this was a way to sidestep the natural controls that regulate stem cell function during tumor development.

"This requirement for both receptors explains why mice engineered to have only LRP6 are resistant to Wnt-mediated tumors," Alexander says. "We think that the Wnt ligand normally responsible for maintaining mammary stem cells falls into the group of ligands that is dependent on both LRPs."

Alexander theorizes further that the dual-action signaling may occur through some pathway that is completely different than the traditional so-called canonical pathway.

To see clearly how LRP5 and LRP6 act singly and together, the team employed a novel technique called IFAST, which works even when natural receptor concentrations are low. The technique was developed by CCC researcher Dr. David Beebe, a UW professor of biomedical engineering.

The technique showed that LRP5 and LRP6 are linked structurally in a single signaling complex, called a heterodimer. Nobody has been able to make such an observation until now.

The dual-requirement for LRP5 and LRP6 was also observed in live mice that had the first stages of tumor growth, which depends on early ductal stem cell activity.

Pharmaceutical companies that produce breast-cancer drugs have focused most of their efforts on the Frizzled receptor and the more traditional canonical signaling pathway it uses. But that may change in the near future, Alexander says.

"Having a different Wnt receptor complex and signaling pathway is something drug companies would be interested in," she says.


'/>"/>

Contact: Dian Land
dj.land@hosp.wisc.edu
608-261-1034
University of Wisconsin-Madison
Source:Eurekalert

Related medicine news :

1. Night Shift Might Boost Womens Breast Cancer Risk: Study
2. Fitness May Boost Survival for Women With Breast Cancer
3. Breast MRI helps predict chemotherapys effectiveness
4. Breast cancer clinical trial tests combo of heat shock protein inhibitor and hormonal therapy
5. Dieting May Lower Hormone Levels Tied to Breast Cancer
6. Discovery suggests new combination therapy strategy for basal-like breast cancers
7. Fox Chase researchers find no disparities in imaging before breast cancer surgery
8. Hybrid vaccine demonstrates potential to prevent breast cancer recurrence
9. Breast cancer effectively treated with chemical found in celery, parsley by MU researchers
10. Scientists discover marker to identify, attack breast cancer stem cells
11. Cancer vaccine combination therapy shows survival benefit in breast cancer
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:3/29/2017)... ... March 29, 2017 , ... The Professional Squash Association, the ... New York City-based sports and entertainment marketing firm Leverage Agency as its exclusive ... the Professional Squash Association (PSA), which includes first-time ever title sponsorship, naming rights, ...
(Date:3/29/2017)... ... March 30, 2017 , ... Youth Futures International (YFI) premiered its Serve, ... high school and college students who have participated in the program every summer. ... is now accepting applications for enrollment. Visit http://www.ghana.yfiexperience.org to learn more. ...
(Date:3/29/2017)... Louisiana (PRWEB) , ... March 29, 2017 , ... ... in three Hours at a Walgreens store in Mississippi. AngioGenesis Labs, makers of ... Walgreens Stores in two southeastern states. Ingredients in HeartBoost, an over the counter ...
(Date:3/29/2017)... ... March 29, 2017 , ... Dr. Angela Cotey, a noted general dentist ... new pediatric patients, with or without a referral. Dr. Cotey knows that interceptive ... outcome and experience. When patients receive early treatment, they may achieve straight teeth with ...
(Date:3/29/2017)... , ... March 29, 2017 , ... Curio Wellness ... to announce the finalization of the company’s executive management team with prominent executives from ... operations is Curio Wellness’ Chief Operating Officer, Ted Dumbauld , who has more ...
Breaking Medicine News(10 mins):
(Date:3/29/2017)... , Mar. 29, 2017 Research and Markets ... 2017-2021" report to their offering. ... The global lifestyle drugs market to grow ... The report, Global Lifestyle Drugs Market 2017-2021, has been prepared ... The report covers the market landscape and its growth prospects over ...
(Date:3/29/2017)... ALTO, Calif. , March 29, 2017 Varian ... it will report results for the second quarter of fiscal ... April 26, 2017.  The news release will be followed by ... PT.  The news release and a link to the conference ... www.varian.com/investor .  To access the teleconference call and replay: ...
(Date:3/29/2017)... JOSE, Calif. , March 29, 2017  Designers ... now significantly reduce solution size by 50% and extend ... Q ) power management integrated circuit (PMIC) from Maxim ... wearable PMIC supports a low input voltage of just ... Zinc Air and Silver Oxide, as well as the ...
Breaking Medicine Technology: