Science Current Events | Science News | Brightsurf.com
 
Email a Friend Send to a friend
Printer Friendly Print CSHL scientists identify new drug target against virulent type of breast cancer

CSHL scientists identify new drug target against virulent type of breast cancer

August 26, 2008

The enzyme target, Brk, is shown to be an accelerator of HER2-positive tumors

Tumor cells in a particular subset of breast cancer patients churn out too much of a protein called ErbB2 -- also often called HER2 -- which drives the cells to proliferate unchecked. Patients unlucky enough to be in this group -- about one in four -- have poorer prognoses and clinical outcomes than those who don't.




The drugs Herceptin and Lapatinib, prescribed in combination with other chemotherapeutic agents, have improved this picture significantly, but leave plenty of room for improvement: they suppress ErbB2 but are effective against less than half of ErbB2-producing tumors. Moreover, patients with tumors that do respond usually develop resistance to these drugs.

A team of scientists at Cold Spring Harbor Laboratory has just published research identifying an enzyme called Brk that may serve as a target for future drugs developed to fight ErbB2-positive tumors. Brk, they report, helps these tumors become virulent and is also implicated in the process through which the tumors develop drug resistance.

The search for co-conspirators

"The limited success of existing therapy suggested to us that factors besides ErbB2, or proteins that collude with ErbB2, might nullify the effects of Herceptin and Lapatinib," explained CSHL Professor Senthil Muthuswamy, Ph.D., leader of the research team and corresponding author of the paper, published online August 21 ahead of print in Proceedings of the National Academy of Sciences.

In the hunt for ErbB2's co-conspirators, Dr. Muthuswamy's team focused on Brk, which they knew to be over-produced in many other types of cancer, including two-thirds of all breast cancers. A detailed analysis of changes that occurred in the genomes of a sample of breast cancer patients helped the group confirm that the expression of ErbB2 and Brk was directly linked.

By forcing the production of both ErbB2 and Brk within the same cell, they determined how Brk enhances ErbB2 activity and fortifies tumor cells against ErbB2-targeting drugs. "Our results might explain why the strategy of using ErbB2 inhibitors alone to treat breast cancers has fallen short," noted Dr. Muthuswamy. "These findings may also suggest a way to treat patients with advanced ErbB2-positive tumors and those who've developed resistance to ErbB2 inhibitors - an idea that we're eager to test."

ErbB2 and Brk go hand-in-hand

ErbB2 is a member of a family of enzymes called receptor tyrosine kinases -- cell-surface molecules that goad cells into proliferating when they sense growth cues in the environs of cells that express them. It turns out that the over-production of ErbB2 in breast cancers is due to a gene mutation that results in the accumulation of multiple copies of the erbB2 gene.

Other genes that undergo such "amplification" due the duplication of DNA segments include brk, which is the gene that instructs cells to manufacture the enzyme Brk. This enzyme is absent in healthy cells but is found at high levels in a majority of breast cancers. As some of these cancers also over-express ErbB2, the CSHL team wondered whether the offending genes, erbB2 and brk, are mutated in tandem, or "co-amplified." This idea in turn raised the possibility that the proteins encoded by these genes are also co-activated and feed into the same proliferation-promoting pathway.

The team checked breast cancer tissue from more than two hundred patients for variations in the number of copies of both genes and found that they were both amplified abnormally in a significant number of these samples. Re-analyzing the samples for the expression levels of both genes revealed that "co-amplified" genes were also "co-overexpressed" -- they were the source of abnormally high levels of their corresponding proteins.

Brk acts as an accelerator of proliferation

Further experiments by Muthuswamy's team revealed that although Brk does not induce cancerous proliferation on its own, it enhances the proliferation of cells that also express ErbB2 by speeding up their entry into the cell cycle. Proliferation in cancer is the result of the cell cycle gone out of control -- beyond limits that healthy cells impose on their own multiplication.

Dr. Muthuswamy likened the cooperation between the Brk and ErbB2 proteins to that between factors that propel a car. "If ErbB2 is the accelerator that makes the car move, Brk helps shift the gear to gain more speed," he explained.

How Brk is implicated in drug resistance

Aside from hurrying along tumor progression, Brk was also found to diminish the effectiveness of ErbB2-inhibiting drugs on tumor growth. This finding reinforces the need for combination therapies. "We might need to hit ErbB2-expressing cancers with drugs against both ErbB2 and Brk," said Muthuswamy.

Brk-inhibitors might also be useful on their own. The CSHL scientists speculate that these drugs might fight tumors that never react to or become resistant to ErbB2-inhibitors.

Targeting Brk is also a safe strategy, according to the scientists, because "Brk does not promote the proliferation of normal cells, and its expression in normal tissues is restricted to non-proliferating cells." Inhibiting this protein might thus "produce fewer unwanted side effects than (targeting) other cancer-promoting proteins" which may be present in larger numbers.

The scientists have also thought up other ways of putting their discovery of the role of Brk in cancer progression to good use. "We also think that Brk would be an ideal clinical marker than could be used to provide both a diagnosis and prognosis for breast cancer," said Dr. Muthuswamy.

Cold Spring Harbor Laboratory



Related Breast Cancer Current Events and Breast Cancer News Articles Breast Cancer Current Events and Breast Cancer News RSS Breast Cancer Current Events and Breast Cancer News RSS
Menopause-cardiology consensus statement on cardiovascular disease and on HRT
A menopause-cardiology consensus statement has called for direct action to prevent cardiovascular disease (CVD) in menopausal women. The statement also concludes that there is little evidence of increased CVD risk in taking HRT.

Researchers Identify Role of Gene in Tumor Development, Growth and Progression
Virginia Commonwealth University Massey Cancer Center and VCU Institute of Molecular Medicine researchers have identified a gene that may play a pivotal role in two processes that are essential for tumor development, growth and progression to metastasis.

UCLA researchers create 'fly paper' to capture circulating cancer cells
Just as fly paper captures insects, an innovative new device with nano-sized features developed by researchers at UCLA is able to grab cancer cells in the blood that have broken off from a tumor.

Fertility procedures need not delay breast cancer treatment for younger women
A new study published in the November issue of the Journal of the American College of Surgeons shows that breast cancer patients under 40 years old who undergo fertility preservation do not face a significant delay in the treatment of their disease when their care is coordinated in a timely fashion.

Coffee break: Compound brewing new research in colon, breast cancer
A compound in coffee has been found to be estrogenic in studies by Texas AgriLife Research scientists.

Drugs to treat anemia in cancer patients linked to thromboembolism
Medications frequently given to cancer patients to reduce their risk of anemia are associated with an increased risk of deep vein thrombosis or pulmonary embolism, according to new research led by Dawn Hershman, M.D, M.S., co-director of the breast cancer program at the Herbert Irving Comprehensive Cancer Center at NewYork-Presbyterian Hospital/Columbia University Medical Center.

Discovery in worms by Queen's researchers points to more targeted cancer treatment
Researchers at Queen's University have found a link between two genes involved in cancer formation in humans, by examining the genes in worms. The groundbreaking discovery provides a foundation for how tumor-forming genes interact, and may offer a drug target for cancer treatment.

FDA approved leukemia drugs shows promise in ovarian cancer cells
The drug Sprycel, approved for use by the U.S. Food and Drug Administration in patients with chronic myeloid leukemia, significantly inhibited the growth and invasiveness of ovarian cancer cells and also promoted their death, a study by researchers with UCLA's Jonsson Comprehensive Cancer Center found.

Carnegie Mellon researchers link health-care debate to risk of dying in US and Europe
The current health care debate in the United States is complicated. Trade-offs between heath care expenditures, lifestyle choices and life expectancy have been suggested but seldom clearly demonstrated.

Scientists uncover new key to the puzzle of hormone therapy and breast cancer
The use of postmenopausal hormone therapy has decreased over time in the United States, which researchers suggest may play a key role in the declining rate of atypical ductal hyperplasia, a known risk factor for breast cancer.
More Breast Cancer Current Events and Breast Cancer News Articles
New Balance Women's Lace Up X Out Breast Cancer Tech Tee (Athletic Grey, Small)

New Balance Women's Lace Up X Out Breast Cancer Tech Tee (Athletic Grey, Small)
by New Balance

The New Balance X Out Breast Caner Tee has a soft hand and clearly states how everyone feels!

1149 WOMENS VINTAGE BLACK ADJUSTABLE FATIGUE CAP w/PINK STRIPES & ''BREAST CANCER'' RIBBON

1149 WOMENS VINTAGE BLACK ADJUSTABLE FATIGUE CAP w/PINK STRIPES & ''BREAST CANCER'' RIBBON
by Rothco

A portion of these proceeds go to the Babylon Breast Cancer Coalition- For Life, For Hope, For Change, For the Future Visit www.babylonbreastcancer.org for more information.

Just Get Me Through This!: The Practical Guide to Breast Cancer

Just Get Me Through This!: The Practical Guide to Breast Cancer
by Deborah A. Cohen (Author), M.D., Robert M. Gelfand (Author)



Fox Run Breast Cancer Awareness Baking Set

Fox Run Breast Cancer Awareness Baking Set
by Fox Run

Support Breast Cancer awareness in a sweet way with this five piece set. Bake cookies using the ribbon cookie cutters or cupcakes using the white paper bake cups with the pattern of pink ribbons. Decorate both with the included 4 in 1 sprinke assortement jar. The set also includes a pink silicone spoon spatula to help mix up your favorite batch of cookie dough.

Breast Cancer Awareness Ribbon Promise of a Cure Cuff Bracelet

Breast Cancer Awareness Ribbon Promise of a Cure Cuff Bracelet
by Silver Insanity

This Cuff Bracelet Will Fit up to a 8" Wrist and is 3/8" Wide Crafted of a Silver Toned Base Metal and Brought to High Polish Shine Set with a Bright Pink Breast Cancer Awareness Ribbon and Inscribed With The Phrase "Promise of a Cure"

Wrangler Women's Tough Enough To Wear Pink Breast Cancer Awareness Jacket,Pink,X-Large

Wrangler Women's Tough Enough To Wear Pink Breast Cancer Awareness Jacket,Pink,X-Large
by Wrangler

Are you tough enough to wear pink? That is the question the western industry asked 12/9/05 at the Wrangler National Finals Rodeo (Wrangler NFR), the "Super Bowl of pro rodeo," as it launched Tough Enough to Wear Pink (TETWP). TETWP is a multi-year, western-industry-wide fundraiser to raise awareness and funds for breast cancer research. TETWP partners are ponying up to support this cause by manufacturing pink merchandise with proceeds benefiting breast cancer research. By wearing this Tough Enough to Wear Pink shirt you are helping in the fight against breast cancer. This TETWP shirt is a pink cotton plaid. Import. Tough Enough to Wear Pink. long sleeve zip front jacket with zippered front slash pockets and the breast cancer embroidery on left chest. 100% Polyester Fleece/100% Nylon...

Raymond Geddes National Breast Cancer Foundation Pen (67709)

Raymond Geddes National Breast Cancer Foundation Pen (67709)
by Raymond Geddes

Breast Cancer Awareness Pen, Join Geddes in supporting the National Breast Cancer Foundation and the fight against Breast Cancer. Assortment contains pink pens with pink ribbons. Retractable, black in pen ink. 5 1/2" long.

Chicken Soup for the Breast Cancer Survivor's Soul: Stories to Inspire, Support and Heal (Chicken Soup for the Soul)

Chicken Soup for the Breast Cancer Survivor's Soul: Stories to Inspire, Support and Heal (Chicken Soup for the Soul)
by Jack Canfield (Author), Mark Victor Hansen (Author), Mary Olsen Kelly (Author)

Your support group in a book, filled with boundless strength and profound hope - until the fight is won.

Along with the shock, fear and loss many women face upon a breast cancer diagnosis comes unexpected strength, wisdom, and strong networks of sharing, support and healing. In Chicken Soup for the Breast Cancer Survivor's Soul, survivors and their family members talk openly about how difficult their fight with breast cancer has been and how they made it through the dark times with a belief in a higher power and the support of those closest to them.

Find strength in the encouraging stories of how family members confront their fears and show genuine affection for one another through gestures such as a granddaughter cutting the hair off of all her dolls so that they will...

Find the Cure Pink Breast Cancer Awareness Wristband

Find the Cure Pink Breast Cancer Awareness Wristband
by sci

Find The Cure Pink Breast Cancer Awareness wristband

Sunbeam Camelot Microplush Heated Throw, Breast Cancer Awareness Pink

Sunbeam Camelot Microplush Heated Throw, Breast Cancer Awareness Pink
by Sunbeam

Soft comfortable fabric that you can cuddle up with anywhere in your house. Use it on the couch while curling up to read a good book or in a chair while watching your favorite show. This throw is 50"x60", with a primstyle control which features 3 warming settings and 3 hour auto-off. So turn on your warming blanket, turn off your thermostat and save on your heating bill. Warm up to a good cause! Sunbeam is joining the fight against breast cancer. Through the purchase of this pink throw, sunbeam will donate $1.00 to city of hope for breast cancer research, treatment and education* up to $25,000. Program ends april 30, 2009. "to save lives and end breast cancer forever by empowering people, ensuring quality care for all, and energizing science to find the cures." *to learn more about...

© 2009 BrightSurf.com