Protease may help define new subset of TNBC—and lead to treatment.

Researchers at St, Louis University have  found a molecular signature that may define a particular subset of triple-negative breast cancer,  which can ultimate lead to target therapy for that group of patients.  In specific, they have uncovered a pathway responsible for the loss of 53BP1 in TNBC tumors related to the  BRCA1 mutation. Loss of BRCA1, they discovered,  increases the expression of the protease cathepsin L (CTSL), which causes the degradation of 53BP1. Cells that have lost both BRCA1 and 53BP1 have the ability to repair DNA and proliferate. That means the protease helps cancer cells with faulty BRCA1 survive—it is a defined bad guy in TNBC growth.  And, when we know who the bad guy is, we can stop looking at ways to stop him in his mean old tracks.

The research was published in the Journal of Cell Biology January 17, 2013.

Treatment of BRCA1-deficient tumor cells with vitamin D restores high levels of 53BP1 slows the growth of cancer cells, they discovered.  In addition, vitamin D treatment might restore the sensitivity to PARP inhibitors in patients who become resistant. Thus, a combination of vitamin D and PARP inhibitors could be effective treatment for some TNBC patients.

They also found that some TNBC tumors have:
• high levels of nuclear CTSL
• low levels of 53BP1 and nuclear vitamin D receptor (VDR)

These unique biomarkers can be used for personalized treatment, identifying those who might benefit the most from vitamin D.

Clinical trials are underway to develop  vitamin D and cathepsin inhibitors as single agents or in combination with different drugs.

Please consider a donation to Positives About Negative to keep this site going.  This work is entirely supported by readers.  Just click on the Donate button in the right of the page.  Thank you!

Read more about TNBC in my book, Surviving Triple-Negative Breast Cancer.

Join Cure's Facebook chat on lifestyle changes to reduce risk of recurrence

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Join CURE in a one-hour discussion on how to make lifestyle changes that will improve your quality of life and help lower recurrence risk.

When: Thursday, Jan. 24, 12 p.m. CT (10 a.m. PT/1 p.m. ET)
Where: CURE's Facebook page

RSVP for the event and submit questions for
"Making Lifestyle Changes to Improve Well-Being, Reduce Recurrence"

Even small changes in diet and physical activity have been shown to reduce risk for some cancers, in addition to reducing fatigue, boosting immunity and improving overall well-being.

Our guests will include Stacy Kennedy, a certified specialist in oncology nutrition, and Russell Kennedy, a behavioral specialist. The Kennedys will offer tips and advice on how to modify behavior and lifestyle and how to maintain a healthy diet.

We'd love to hear your questions and have you share your story with us. You can submit questions on the Event page or email them to us at editor@curetoday.com. Please join us and other readers for this very informative chat with experts in the field, patients, survivors and caregivers.

New sequencing may simplify BRCA testing and highlight most aggressive mutations

PHILADELPHIA — A new multiple gene expression profile test was able to predict the presence of harmful BRCA1 or BRCA2 mutations in otherwise healthy women carrying the mutations, according to data published in Cancer Prevention Research, a journal of the American Association for Cancer Research.

“This novel technology aims to provide a layer of information regarding the cell functionality aspect of BRCA mutations that could greatly enhance the doctor’s ability to identify high-risk carriers,” said Asher Y. Salmon, M.D., a breast cancer specialist at the Hadassah Hebrew University Medical Center in Jerusalem, Israel.

Women with a mutation in their BRCA1 or BRCA2 gene have a significantly increased risk for developing breast cancer or ovarian cancer, and for many of those at risk disease may develop at an early age. Researchers are investigating ways to detect these genetic mutations so women carrying the genes can consider taking measures to reduce their cancer risk or increase the chance for detecting cancer in its early stages.

“The current tool for mutation detection is gene sequencing, which is expensive, time-consuming and, in many cases, lacking clear and decisive clinical decision making information,” said Salmon. “In many cases, the current sequencing tool identifies a mutation, but we do not know if the mutation is neutral or harmful.”

According to Salmon, emerging evidence has revealed that cells with a mutation in one of the two copies of the BRCA1 or BRCA2 genes have a distinct gene expression profile when exposed to causes of DNA damage, such as radiation.

After collecting white blood cells from blood samples donated by nine healthy women with a mutated BRCA1 gene and eight healthy women with a mutated BRCA2 gene, Salmon and his colleagues cultured the cells and exposed them to radiation. They then extracted the total RNA from these cells and compared it to the total RNA from identically treated white blood cells from 10 healthy, noncarrier women.

About 1,500 genes were differentially expressed between carriers and noncarriers. They narrowed this list to 18 genes that were the most significantly differentiated between the two groups of women. The final narrowing was done with a validation study of a model using 21 of the newly identified genes and five control genes to predict the risk for carrying a mutation. They used blood samples from an independent group of 40 women who were carriers of mutated BRCA1 and/or BRCA2 and 17 noncarrier women. The model had a sensitivity of 95 percent and a specificity of 88 percent.

According to Salmon, this test can portray whether a patient carries a harmful mutation regardless of the patient’s ethnic origin or specific mutation. In addition, it is affordable and quick, he said.

“In wealthy societies, it can become a screening tool for identifying individuals with a very high susceptibility for carrying a mutation, and full sequencing can be reserved only for them,” Salmon said. “In societies in which sequencing is not feasible, this test can substitute for it with a very high accuracy rate.”

Salmon and colleagues are assembling a large validation study in Europe and North America to analyze the efficacy of the test in heterogeneous populations.

Please consider a donation to Positives About Negative to keep this site going.  This work is entirely supported by readers.  Just click on the Donate button in the right of the page.  Thank you!

Read more about TNBC in my book, Surviving Triple-Negative Breast Cancer.

Relax: Imagine yourself in one of those chairs

Near Kona, Hawaii.  Photo by Pat

Scientists Map TNBC's Metastatic Path

Cancer Scientists at Weill Cornell Medical College have discovered the molecular switch that allows triple negative breast cancer cells to grow the amoeba-like protrusions they need to crawl away from a primary tumor and metastasize throughout the body. Their findings, published in Cancer Cell, suggest a novel approach for developing agents to treat cancer once it has spread.

"Metastasis can be lethal, and our findings point to potential targeted treatments to stop the spread of this aggressive breast cancer," says the study's senior investigator, Vivek Mittal, MD, an associate professor of cell and developmental biology and director of the Lehman Brothers Lung Cancer Laboratory at Weill Cornell Medical College. 

According to researchers, if such agents were developed, they would perhaps be the first to specifically treat cancer metastasis in patients whose tumors have already spread. They would also be among the first designed to restore the function of a microRNA (miRNA), a small, non-coding RNA that regulates gene expression, which is crucial to cancer spread. While distinct miRNA "signatures" have been found for many tumor types, including different breast cancers, their specific roles in later steps of cancer metastasis has been unclear, Dr. Mittal says.

In the study, researchers set out to identify a miRNA that impacts metastasis without affecting primary tumor growth, as well as address its underlying molecular mechanisms and therapeutic potential against metastatic breast cancer. They discovered that a miRNA known as miR-708 is inhibited in metastatic triple negative breast cancer. They found that miR-708 acts as a metastatic tumor inhibitor, and when its function is restored, the tumors do not spread or form lethal macrometastases. 

Using genome wide miRNA sequencing, Dr. Mittal and his research team found in human samples of triple negative breast cancer that miR-708 was significantly down-regulated with its normal expression curtailed. In both laboratory cells and in animal studies, the researchers identified that the normal role of miR-708 is to suppress the protein neuronatin, which is located on the membrane of a cell's endoplasmic reticulum—an organelle that stores calcium. Neuronatin helps control how much calcium leaves that organelle. 

"It is calcium that provides legs to cancer cells to help them escape a tumor. So miR-708 acts as a suppressor of metastasis by keeping neuronatin in check," Dr. Mittal says. "If miR-708 is itself suppressed, there is an increase in production of neuronatin proteins, which then allows more calcium to leave the endoplasmic reticulum and activate a cascade of genes that turn on migratory pathways leading to metastasis."

 Researchers found that delivering synthetic miR-708, carried by bubbles of fat, blocked metastatic outgrowth of triple negative breast cancer cells in the lung of mice. This makes miR-708 a promising therapeutic against metastatic breast cancer. The researchers also discovered that polycomb repressor complex proteins are responsible for silencing miR-708. These proteins remodel the way DNA is packaged in order to epigenetically silence genes. Dr. Mittal adds that the findings suggest that pharmacological agents now being tested in lymphoma cancer cells may also help to restore miR-708 in triple negative breast cancer. These drugs are designed to inhibit histone-lysine N-methyltransferase EZH2, the member of the polycomb group that directly silences miR-708.

"These study results are terrific," says co-author Dr. Linda Vahdat, director of the Breast Cancer Research Program, chief of the Solid Tumor Service and professor of medicine at Weill Cornell Medical College and medical oncologist at the Iris Cantor Women's Health Center at NewYork-Presbyterian Hospital/Weill Cornell Medical Center. "It not only offers us an avenue to treat metastatic triple negative breast cancer in the short-term, but also gives us the roadmap to prevent metastases in the long-run. We are anxious to get this into the clinic and are working as quickly as possible towards that end." 

Read more in the journal Cancer Cell.

Please consider a donation to Positives About Negative to keep this site going.  This work is entirely supported by readers.  Just click on the Donate button in the right of the page.  Thank you!

Read more about TNBC in my book, Surviving Triple-Negative Breast Cancer.

Breast Cancer and the Environment

Breast Cancer and Occupational Health: A Discussion of a Canadian Case-Control Study

Historically, there has been a dearth of information on occupational exposures of women to chemicals and endocrine disruptors and therefore on links between occupational exposures and breast cancer specifically.  In November 2012, a landmark paper titled "Breast cancer risk in relation to occupations with exposure to carcinogens and endocrine disruptors: a Canadian case-control study" was published in the journal Environmental Health. In this groundbreaking study the authors showed that across all sectors, women in jobs with potentially high exposures to carcinogens and endocrine disruptors had elevated breast cancer risk and that premenopausal breast cancer risk was highest for automotive plastics and food canning workers. The two key authors of this study, James Brophy, PhD, and Margaret Keith, PhD, will join Jeanne Rizzo, RN, President and CEO of the Breast Cancer Fund and Charlotte Brody, RN, Associate Director, Health Initiatives, BlueGreen Alliance to discuss this study and its implications for the safety of workers and others and on occupational health policy on Tuesday January 8, 2013 at 10:00 am Pacific / 1:00 pm Eastern. Featured speakers include: Jeanne Rizzo, RN, President and CEO of the Breast Cancer Fund. Ms. Rizzo leads the organization's strategic initiatives to remove the chemical bisphenol A, or BPA, from food packaging; to ensure cosmetics are non-toxic; and to overhaul the broken chemicals-management system that allows tens of thousands of toxic and untested chemicals to be used in consumer products. She also guides scientific initiatives, including the 2011 publication of a groundbreaking BPA dietary study. Recent legislative victories include the passage of a federal law banning toxic chemicals linked to breast cancer from toys, and California laws creating the first statewide biomonitoring program, advancing the safety of cosmetics and regulating chemicals in consumer products. Recent victories in the marketplace include a commitment from Campbell Soup Co. to remove BPA from its can linings and from Johnson & Johnson to globally reformulate its cosmetics products to remove harmful chemicals. James Brophy, PhD, and Margaret Keith, PhD, are research--and life partners. Their work together over the past thirty years has focused on a wide range of public health and social justice issues. They earned their doctorates in occupational and environmental health from the University of Stirling in the UK. Together they have led several research studies exploring occupational risk factors for breast cancer. In three completed case-control studies they found evidence of an association between the development of breast cancer and work in several industries including agriculture. Together they have co-authored two widely distributed books: Workplace Roulette: Gambling with Cancer and Barefoot Research: A Worker's Manual for Organizing on Work Security. Both were formerly on staff with the Occupational Health Clinics for Ontario Workers (OHCOW). They have been working for the past two years with the National Network on Environments and Women's Health (NNEWH) at York University, which is exploring breast cancer risks for women employed in plastics manufacturing. Charlotte Brody is the Associate Director for Health Initiatives for the BlueGreen Alliance, a national strategic partnership between labor unions and environmental organizations dedicated to expanding the number and quality of jobs in the green economy. A registered nurse and the mother of two sons, Charlotte previously served as the Director of Programs for Green For All in Oakland, California and the Executive Director of Commonweal. She is a founder and former Executive Director of Health Care Without Harm and on the boards of Bioneers, Clean Production Action, Health Care Without Harm, the Regenerative Design Institute and the National Medical Committee of Planned Parenthood Federation of America. Charlotte has served as a volunteer for the Student Non-violent Coordinating Committee (SNCC) and the GI Coffee House Movement during the War in VietNam. She was a founding staff member of the Carolina Brown Lung Association, the Public Affairs Director and Executive Director of a Planned Parenthood affiliate, and the Organizing Director for the Center for Health and Environmental Justice. The call will be moderated by Steve Heilig, MPH, CHE Director of Public Health & Education, and Director of Public Health & Education, San Francisco Medical Society. The call will last one hour and will be recorded for archival purposes. Please consider a donation to Positives About Negative to keep this site going.  This work is entirely supported by readers.  Just click on the Donate button in the right of the page.  Thank you! Read more about TNBC in my book, Surviving Triple-Negative Breast Cancer.