Nav: Home

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

August 25, 2008

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.
-end-
"Brk is coamplified with ErbB2 to promote proliferation in breast cancer" appeared August 21, 2008 ahead of print in Proceedings of the National Academy of Sciences. The full citation is: Bin Xiang, Kiranam Chatti, Haoqun Qiu, B. Lakshmi, Alexander Krasnitz, Jim Hicks, Min Yu, W. Todd Miller, and Senthil K. Muthuswamy. The paper is available online at: doi: 10.1073/pnas.0805009105

CSHL is a private, non-profit research and education institution dedicated to exploring molecular biology and genetics in order to advance the understanding and ability to diagnose and treat cancers, neurological diseases, and other causes of human suffering.

For more information, visit www.cshl.edu

Cold Spring Harbor Laboratory

Related Breast Cancer Articles:

Does MRI plus mammography improve detection of new breast cancer after breast conservation therapy?
A new article published by JAMA Oncology compares outcomes for combined mammography and MRI or ultrasonography screenings for new breast cancers in women who have previously undergone breast conservation surgery and radiotherapy for breast cancer initially diagnosed at 50 or younger.
Blood test offers improved breast cancer detection tool to reduce use of breast biopsy
A Clinical Breast Cancer study demonstrates Videssa Breast can inform better next steps after abnormal mammogram results and potentially reduce biopsies up to 67 percent.
Surgery to remove unaffected breast in early breast cancer increases
The proportion of women in the United States undergoing surgery for early-stage breast cancer who have preventive mastectomy to remove the unaffected breast increased significantly in recent years, particularly among younger women, and varied substantially across states.
Breast cancer patients with dense breast tissue more likely to develop contralateral disease
Breast cancer patients with dense breast tissue have almost a two-fold increased risk of developing disease in the contralateral breast, according to new research from The University of Texas MD Anderson Cancer.
Some early breast cancer patients benefit more from breast conservation than from mastectomy
Breast conserving therapy (BCT) is better than mastectomy for patients with some types of early breast cancer, according to results from the largest study to date, presented at ECC2017.
One-third of breast cancer patients not getting appropriate breast imaging follow-up exam
An annual mammogram is recommended after treatment for breast cancer, but nearly one-third of women diagnosed with breast cancer aren't receiving this follow-up exam, according to new findings presented at the 2016 Annual Clinical Congress of the American College of Surgeons.
Low breast density worsens prognosis in breast cancer
Even though dense breast tissue is a risk factor for breast cancer, very low mammographic breast density is associated with a worse prognosis in breast cancer patients.
Is breast conserving therapy or mastectomy better for early breast cancer?
Young women with early breast cancer face a difficult choice about whether to opt for a mastectomy or breast conserving therapy (BCT).
Breast density and outcomes of supplemental breast cancer screening
In a study appearing in the April 26 issue of JAMA, Elizabeth A.
Full dose radiotherapy to whole breast may not be needed in early breast cancer
Five years after breast-conserving surgery, radiotherapy focused around the tumor bed is as good at preventing recurrence as irradiating the whole breast, with fewer side effects, researchers from the UK have found in the large IMPORT LOW trial.

Related Breast Cancer Reading:

Dear Friend: Letters of Encouragement, Humor, and Love for Women with Breast Cancer
by Gina L Mulligan (Author)

Chicken Soup for the Soul: Hope & Healing for Your Breast Cancer Journey: Surviving and Thriving During and After Your Diagnosis and Treatment
by Dr. Julie Silver (Author)

Dr. Susan Love's Breast Book (A Merloyd Lawrence Book)
by Susan M. Love (Author), Karen Lindsey (Contributor), Elizabeth Love (Contributor)

Heal Breast Cancer Naturally: 7 Essential Steps to Beating Breast Cancer
by Dr. Veronique Desaulniers (Author)

The Whole-Food Guide for Breast Cancer Survivors: A Nutritional Approach to Preventing Recurrence (The New Harbinger Whole-Body Healing Series)
by Edward Bauman MEd PhD (Author), Helayne Waldman MS EdD (Author), Donald I. Abrams MD (Foreword)

The Breast Cancer Survival Manual, Sixth Edition: A Step-by-Step Guide for Women with Newly Diagnosed Breast Cancer
by John Link M.D. (Author), James Waisman M.D. (Author), Nancy Link R.N. (Author)

Breast Cancer Smoothies: 100 Delicious, Research-Based Recipes for Prevention and Recovery
by Daniella Chace (Author)

Just Get Me Through This! - Revised and Updated: A Practical Guide to Coping with Breast Cancer
by Deborah A. Cohen (Author), Robert M. Gelfand M.D. (Author)

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)

Best Science Podcasts 2018

We have hand picked the best science podcasts for 2018. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Circular
We're told if the economy is growing, and if we keep producing, that's a good thing. But at what cost? This hour, TED speakers explore circular systems that regenerate and re-use what we already have. Guests include economist Kate Raworth, environmental activist Tristram Stuart, landscape architect Kate Orff, entrepreneur David Katz, and graphic designer Jessi Arrington.
Now Playing: Science for the People

#504 The Art of Logic
How can mathematics help us have better arguments? This week we spend the hour with "The Art of Logic in an Illogical World" author, mathematician Eugenia Cheng, as she makes her case that the logic of mathematics can combine with emotional resonance to allow us to have better debates and arguments. Along the way we learn a lot about rigorous logic using arguments you're probably having every day, while also learning a lot about our own underlying beliefs and assumptions.