Enzyme Kills TNBC And Spares Non-Cancerous Cells

Targeting a specific enzyme—O-GlcNAc transferase (OGT)— can kill triple-negative breast cancer cells but spare non-tumor cells, according to a study in the online edition of Molecular Cell.

Researchers discovered that reducing levels of OGT or blocking OGT activity selectively killed cancer cells but spared non-cancer breast cells. This reduces critical metabolites involved in energy production that feeds cancer growth and survival. 

The team showed that TNBC tumors contain higher expression of OGT and HIF-1a compared to other breast cancer subtypes. These results provide evidence that targeting OGT may provide targeted therapy for TNBC.

• Edited from a news release from Drexel University College of Medicine.

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• For more details on TNBC, check out the well-reviewed Surviving Triple-Negative Breast Cancer, which many TNBC survivors call their "bible."

Study Finds Clues to How TNBC Spreads

Researchers have identified chemical signals that triple-negative breast cancer cells use to recruit two types of normal cells needed for the cancer’s spread. The study, which was done on mice, appears in the online early May edition of the Proceedings of the National Academy of Sciences.

The research focused on a chemical signal called hypoxia-inducible factor 1 (HIF-1), which cells release to help them cope with low-oxygen conditions. Earlier, the group determined that HIF-1 helps breast tumor cells survive the low-oxygen conditions in which they often live, and spread to other parts of the body such as the lungs. "In breast cancer, it's not the original tumor that kills patients, but the metastases," says Gregg Semenza, M.D., Ph.D., a professor and director of the Vascular Biology Program in the Johns Hopkins University School of Medicine's Institute for Cell Engineering.

All of the breast cancer cells used in the study were triple-negative, which have been shown in previous research to contain more HIF-1 than other types of breast cancers.

"This study adds to the evidence that a HIF-1 inhibitor drug could be an effective addition to chemotherapy regimens, especially for triple-negative breast cancers," Semenza says. Several potential drugs of this kind are now in the early stages of development, he notes.

"Blocking one of these cell-recruiting signals in a mouse's tumor made it much less likely to metastasize or spread," Semenza says. "If a drug can be found that safely blocks the same signal in humans, it could be a very useful addition to current treatment—particularly for patients with chemotherapy-resistant tumors."

Also in a previous study, Semenza's group found that HIF-1 induced adult mesenchymal stem cells to release a signal to nearby breast cancer cells, which made them more likely to spread. The researchers suspected this communication might run both ways and that the stem cells' presence might also help the cancer to recruit the host animal's white blood cells. Breast cancers need the support of several types of host cells in order to metastasize, including mesenchymal stem cells and one type of white blood cell, Semenza notes.

Studying tumor cells grown in a dish, Semenza's team used chemicals that blocked the functions of various proteins to map a web of signals between breast cancer cells, menenchymal stem cells and white blood cells. One positive feedback loop brought mesenchymal stem cells close in to the breast cancer cells. A separate loop of signals between the stem cells and cancer cells caused the cancer cells to release a chemical "beacon" that drew in white blood cells.

The concentrations of all the signals in the web were increased by the presence of HIF-1—and ultimately, by low-oxygen conditions.

The team then used genetic engineering to reduce the levels of the cell-recruiting signals in breast cancer cells and implanted those cells into female mice. Compared with unaltered breast cancer cells, those with reduced recruiting power grew into similar-sized tumors, Semenza says, but were much less likely to spread.

From a news release from the Johns Hopkins University School of Medicine.

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Newly Diagnosed with Breast Cancer? Some Questions to Ask the Doc

Understanding your diagnosis is key to understanding your treatment.   To decide the right path for you, use the questions below as the start of your discussion.  Always ask how a treatment affects you specifically—if your doctor sounds like he is offering a cookie-cutter approach, it is time for a second opinion.  No two women are the same; no two diseases are identical. 

What clinical stage is my tumor? And what are the implications of that stage? Early stage breast cancer is typically stage 1 and 2.  Stage 3 means either a larger tumor or affected lymph nodes.  Stage 4 is metastatic breast cancer, meaning the disease has spread beyond the breast and nodes, usually to the bones, lungs, brain, or liver.

What kind of surgery do you recommend and why?  Why is that choice specifically better for me?  If your surgeon recommends a mastectomy, ask for data that show that this approach is better for you than a lumpectomy.  If, in contrast, you worry that a lumpectomy is enough, ask for data on its effects on your specific diagnosis.

Do I need chemotherapy? If so, should I have it before or after surgery?  If I have it before, and the tumor responds to the chemo, what surgery would you plan afterward?

What is my prognosis with chemo?  What is my prognosis without chemo?  How will my individual risk be reduced?  What is my individual risk of recurrence without chemo, what is my risk of recurrence with chemo?

What chemo drugs do you use and why?

Do you have literature on those drugs, their effects, and their side effects?  If he says, “We have taken care of the side effects,” as one doctor told me, challenge that statement.  They have not taken care of the side effects.

What type of radiation do you suggest? Is accelerated partial breast irradiation an option?  What is its success potential in my specific case?  Is whole breast radiation better?  If so, why?

What about reconstruction? Will I need it?   Do you recommend it?  If so should I have it done immediately or should I delay it until after treatment?

Can I talk to other women who have gone through this treatment?  Hearing from actual women is good.  This does not necessarily mean a support group—it means being able to call a smart woman who has already walked this road and talk with her about how that feels.

• This is an excerpt from Surviving Triple-Negative Breast Cancer, which includes additional details on staging and treatment, including chemotherapy, radiation, and surgery.

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Leukemia Drug Could Be Targeted Therapy for TNBC

A drug used to treat leukemia patients shows promise in fighting triple-negative breast cancer, according to a study published in PLOS ONE.

The drug imatinib mesylate targets a protein  found in roughly half of the TNBC tumor samples tested and stops the growth process.

“The next step is to organize a phase one clinical trial, where we would test this drug in a small number of women with this cancer subtype in addition to their regular treatment. We hope to be able to start that process shortly,” said Dr. Wael M. ElShamy, associate professor of biochemistry and researcher at the University of Mississippi Medical Center.

If the drug imatinib passes clinical trials, it would be a new targeted therapy for TNBC.  It already has Food and Drug Administration approval for use in humans so that could speed its use for TNBC.  Oncologists currently prescribe imatinib for children and adults with certain types of leukemia.

Read the full news release from the University of Mississippi Medical Center.

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Nanoparticles May Replace Chemo and Radiation

Using magnetically controlled nanoparticles to force tumor cells to self-destruct could be a future part of cancer treatment—replacing chemotherapy—according to research from Lund University in Sweden. The technique is much more targeted and less harmful than trying to kill cancer cells with toxic techniques such as chemotherapy, which damages other cells and radiation, which affects surrounding tissue.

The research, published in the journal ACD Nano, is a collaboration between physicists, chemists, engineers and doctors from Sweden, Germany and the United States.  

“Our technique is able to attack only the tumor cells," said Enming Zhang, one of the first authors of the study.

The technique places the nanoparticles into a tumour cell, where they bind to lysosomes, which break down foreign substances that have entered a cell and can also break down the entire cell.

Researchers used nanoparticles of iron oxide treated with a special form of magnetism. Once the particles are inside the cancer cells, the cells are exposed to a magnetic field, and the nanoparticles begin to rotate in a way that causes the lysosomes to start destroying the cells.

Previous research on supermagnetic nanoparticles has focused on using the magnetic field to create heat that kills the cancer cells.  But this can cause inflammation that risks harming surrounding, healthy tissue. The method developed at Lund  only affects the tumor cells that the nanoparticles have entered.

While primarily intended for cancer treatment, the technique can also be applied to autoimmune diseases such as type 1 diabetes, in which the immune system attacks the body’s own insulin production.

The researchers at Lund University have a patent pending for their technique with rotating nanoparticles, although they acknowledge that  work remains before it can be transferred from the laboratory to clinical trials on patients.

—Information from a news release from Lund University.

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Vegetables and Fruits Show Benefits for ER-negative Breast Cancer

Eating fruits and vegetables reduced the risk of estrogen-negative breast cancer, even though it had no effect on other kinds of breast cancer, according to a study that analyzed research from 20 previous studies and published in the Journal of the National Cancer Institute. Vegetables were slightly better than fruits.

Because researchers were looking at studies that had already been done, they could not control the types and amounts of vegetables and fruits that were studied.  Some of the studies, though, have shown that five servings a day are beneficial, with no added benefit for more than that.  This includes broccoli, cabbage and other cruciferous vegetables, plus apples, pears, peaches, nectarines, apricots, strawberries, carrots, and lettuce.

Researchers noted that, because of their "high protein or starch content," mature beans and potatoes were excluded. Pickled fruit and vegetables were also excluded "because they contain potentially carcinogenic nitrates and preservatives."

Data were analyzed on 24, 673 breast cancer survivors; 4821 of these were estrogen-negative.  Because not all studies included Her2 status, researchers did not specifically consider cases of TNBC, although other research shows that results from ER-negative studies often translate to TNBC cases.

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New Genetic Pathway Linked to TNBC

Scientists from Houston Methodist and Weill Cornell Medical College have found that a gene previously unassociated with breast cancer plays a pivotal role in the growth and progression of triple negative breast cancer. Their research, published in the April 3 Nature (online today), suggests that targeting the gene may be a new approach to treat the disease.

"We are really beginning to understand what initiates the cancer and why cancer cells evade treatment," said coauthor and Houston Methodist Cancer Center Director Jenny Chang, M.D. "Our group learned this pathway was activated in about two-thirds of patients with this type of breast cancer, and we believe we may be able to treat the disease by manipulating elements of the pathway."

About 42,000 new cases of triple negative breast cancer (TNBC) are diagnosed in the United States each year, about 20 percent of all breast cancer diagnoses. If patients relapse, they typically do so within one to three years of being treated.

Using cells taken from patients' tumors and transplanted into mice, researchers found that the gene, XBP1, is especially active in TNBC, particularly in the progression of malignant cells and their resurgence after treatment.

"Patients with the triple negative form of breast cancer are those who most desperately need new approaches to treat their disease," said senior author Laurie H. Glimcher, M.D., professor of medicine at Weill Cornell. "This pathway was activated in about two-thirds of patients with this type of breast cancer. Now that we better understand how this gene helps tumors proliferate and then return after a patient's initial treatment, we believe we can develop more effective therapies to shrink their growth and delay relapse."

The group, which included investigators from nine institutions, examined several types of breast cancer cell lines. They found that XBP1 was particularly active in basal-like breast cancer cells cultivated in the lab and in TNBC cells from patients. When they suppressed the activity of the gene in laboratory cell cultures and animal models, however, the researchers were able to dramatically reduce the size of tumors and the likelihood of relapse, especially when these approaches were used in conjunction with the chemotherapy drugs doxorubicin or paclitaxel. The finding suggests that XBP1 controls behaviors associated with tumor-initiating cells that have been implicated as the originators of tumors in a number of cancers, including that of the breast, supporting the hypothesis that combination therapy could be an effective treatment for TNBC.

The scientists also found that interactions between XBP1 and another transcriptional regulator, HIF1-alpha, spurs the cancer-driving proteins. Silencing XBP1 in the TNBC cell lines reduced the tumor cells' growth and other behaviors typical of metastasis.

"This starts to demonstrate how cancer cells co-opt the endoplasmic reticulum stress response pathway to allow tumors to grow and survive when they are deprived of nutrients and oxygen," said lead author Xi Chen, Ph.D., a postdoctoral associate at Weill Cornell, referring to the process by which healthy cells maintain their function. "It shows the interaction between two critical pathways to make the cells better able to deal with a hostile microenvironment, and in that way offers new strategies to target triple negative breast cancer."

Scientists still need to study how those strategies would help women with the disease.

"Obviously we need to know now whether what our group saw in models is what we'll see in patients," Chang said. "We are very excited about the prospect of moving this research forward as soon as possible for the benefit of patients."

—Information from a news release from Houston Methodist and Weill Cornell Medical College

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RIP2: A new target for a potential TNBC drug?

The receptor-interacting protein kinase 2 (RIP2),  known to be involved in  inflammatory processes, also has roles in triple-negative breast cancer metastasis, according to a study in the journal Breast Cancer Research.

The research analyzed data from six breast cancer databases, including The Cancer Genome Atlas and determined that RIP2 was significantly overexpressed in TNBC and correlated with worse progression-free survival.

The results suggest that targeting RIP2 may improve outcomes in advanced breast
cancer patients, in which it is over expressed.

It's another target, folks.  And another target might mean a targeted drug.

I do think RIP is an ominous name, but I guess they weren't looking at that.

You can read the entire study here.

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MRI Data Can Spot TNBC Earlier, Speed Treatment

Patterns in magnetic resonance images may predict if a patient has triple-negative breast cancer, slower-moving cancers or non-cancerous lesions with 95 percent accuracy, according to research published online in the journal Radiology.

The technique could enable doctors to use an MRI scan to diagnose more aggressive cancers earlier and fast track these patients for therapy.  

"Literally, what we're trying to do is squeeze out the information we're not able to see just by looking at an image," said senior author Anant Madabhushi, a professor of biomedical engineering at Case School of Engineering and director of the Center for Computational Imaging and Personalized Diagnostics.

Researchers analyzed images from 65 women and discovered that tumors from triple-negative cancer reflect different textures when images are enhanced with contrasting agents.

"Today, if a woman or her doctor finds a lump, she gets a mammogram and then a biopsy for molecular analysis, which can take two weeks or up to a month," Madabhushi said. "If we can predict the cancer is triple-negative, we can fast track the patient for biopsy and treatment. Especially in cases with triple-negative cancer, two to four weeks saved can be crucial."

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How did you feel the year after treatment?

I'd like a little favor from those of you more than a year past treatment:  How did you feel in that first year, once treatment was over?  I have a question about this from a reader—how do other women feel?— and have discovered this has not been that well studied.  There are a lot of "you should feel" suggestions through various cancer organizations, but I have not found any decent actual research.


So I would like us to at least have a discussion of this.  I am lucky to be so far past that first year that my memory is not all that strong, but I do know I was extra tired and had pain in my surgical incisions, and some pain generally around my chest, which I was told was related to radiation.   That pain is gone and cancer has not returned, so whatever it was ended up not being any sort of a threat.  My energy level still is not anything to write home about, but I tend to get a lot done, and I am fairly committed to regular exercise, so I think I am doing just fine.  (Yay!)

So, how did you feel in that first year?  (Or how do you feel, if you're now in that year?)  Do you think you got more colds and other viruses/infections than normal?  Do you feel you had a weakened immune system?  For longer survivors, how long did this last?

There is a lot we can do to keep ourselves healthy, and this reader is already on that—she is eating healthy and maintaining a healthy level of physical activity.  Still, she has been getting a lot of colds and she wants to know if other women feel like she does.  And, even though she did not say it, I think she wants to know if this is going to go away soon.

I'll post this on my Facebook page so you can discuss it there, or you can comment below.

I think we will all feel better once this awful winter is past and we can get our usual doses of natural vitamin D.

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Osteoporosis Drug Evista May Treat TNBC

The osteoporosis drug raloxifene, primarily prescribed for post-menopausal women, may also be able to treat triple-negative breast cancer,  according to research published in Cell Death and Disease.

In lab tests, researchers found that the drug, marketed under the brand name Evista, killed human TNBC cells as well as liver cancer cells.   Raloxifene binds with a protein called the aryl hydrocarbon receptor (AhR) and kills cancer cells that do not have receptors for estrogen.  Included in the study was an analysis of data on women who had estrogen-negative breast cancers, in which researchers found increased survival rates in the women whose breast cancers had higher levels of the AhR protein.

Raloxifene would have to go through clinical trials, showing its effects on women rather than just on cells in the lab, before it can become an approved therapy, but, under the Affordable Care Act, most health insurance plans are now required to offer raloxifene at no cost to women who have an increased risk of developing breast cancer.

Raloxifene belongs to a class of drugs called  selective estrogen receptor modulators (SERMs). Research presented at the San Antonio Breast Cancer Symposium in December 2013 demonstrated that a different class of osteoporosis drugs, bisphosphonates, can reduce the risk of breast cancer recurrence in all types of breast cancer. 

SOURCE:  "The aryl hydrocarbon receptor mediates raloxifene-induced apoptosis in estrogen receptor-negative hepatoma and breast cancer cells." O'Donnell EF, Koch DC, Bisson WH, Jang HS, Kolluri SK. Cell Death Dis. 2014 Jan 30;5:e1038.DOI: 10.1038/cddis.2013.549.

Information from Oregon State University.

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

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One sure thing about winter:  Spring is coming next.

Will Research on the Nuclear Protein Twist Lead to Targeted TNBC Treatment?

A nuclear protein called Twist may provide an effective approach for treating triple-negative breast cancer, according to a recent study published in Cancer Cell.  Twist is an accelerant of the epithelial-mesenchymal transition (EMT) program in human cells, which is significant because TNBC has an activated EMT program. EMT provides tumor cells with stem cell-like characteristics, making them resistant to chemotherapy and increasing their chances for early metastasis.

Researchers found that Twist interacted with a key nuclear transcription regulator, BRD4. When many DNA viruses (such as papillomaviruses) enter into human “host” cells during infection, they hijack host cell machinery to replicate and synthesize their viral DNA and proteins. BRD4 is the virus's favored molecule and is often seized by DNA papillomaviruses for gene transcription during replication and growth.

The study showed that two BRD4 inhibitors, JQ1 and MS417, can specifically disrupt the interaction of Twist with BRD4, resulting in the suppression of triple-negative breast cancer cells.

"This finding has significant clinical ramification, because drugs that can target the Twist-BRD4 interaction provide a new hope for treating life-threatening triple-negative breast cancer," said lead researcher Peter Zhou, associate professor of molecular and cellular biochemistry at the University of Kentucky Markey Cancer Center.  

—Information from a news release from the University of Kentucky

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

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High BMI Linked to TNBC

Significant increases in body mass index are associated with an increased risk of triple-negative breast cancer, according to research published in the journal Cancer, produced by the American Cancer Society.  In the study, women who went up ten points or more—from, for example, a BMI of 22 to one of 32—between the ages of 18 and 44 doubled their risk of TNBC.   There was no increased risk of estrogen-positive breast cancer.

The sampling included women ages 20 to 44 years who were diagnosed from 2004 to 2010 in the Seattle-Puget Sound metropolitan area:
• 779 with estrogen receptor-positive breast cancer
•182 triple-negative breast cancer
• 60 with ER-negative/HER2-overexpressing, invasive breast cancer
• 939 cancer-free controls.  

This supports a fairly large body of research that has associated weight gain with TNBC risk.

Read more about BMI and TNBC, plus a roadmap for a healthy lifestyle, in my book, Surviving Triple-Negative Breast Cancer.

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Is Smoking Associated with TNBC? Yes. Or No. Depends on Which Study You Look At

Young women who smoke and have been smoking a pack a day for a decade or more have a significantly increased risk of developing hormone-positive  breast cancer, but smoking is not related to a woman’s risk of triple-negative breast cancer, according to a new analysis published online in Cancer, a peer-reviewed journal of the American Cancer Society.

The majority of recent studies evaluating the relationship between smoking and breast cancer risk among young women have found that smoking is linked with an increased risk; however, few studies have evaluated risks according to different subtypes of breast cancer.

To investigate, Christopher Li, MD, PhD, of the Fred Hutchinson Cancer Research Center in Seattle, and his colleagues conducted a population-based study consisting of 778 patients with estrogen receptor positive breast cancer and 182 patients with triple-negative breast cancer. 

Patients in the study were 20 to 44 years old and were diagnosed from 2004-2010 in the Seattle-Puget Sound metropolitan area. The study also included 938 cancer-free controls.
The researchers found that young women who were current or recent smokers and had been smoking a pack a day for at least 10 years had a 60 percent increased risk of estrogen receptor positive breast cancer. 

“The health hazards associated with smoking are numerous and well known. This study adds to our knowledge in suggesting that with respect to breast cancer, smoking may increase the risk of the most common molecular subtype of breast cancer but not influence risk of one of the rarer, more aggressive subtypes,” said Dr. Li.

Previous research has also shown that postmenopausal women who smoke do not face an increased risk of TNBC, according to research using data from the Women's Health Initiative. The study enrolled 148,030 women, 300 of whom had TNBC and 2,479 of whom had estrogen-positive disease. Smoking and alcohol use were both associated with ER-positive breast cancer, but not with TNBC. The research was published in Cancer Causes Control (2011).* 

BUT:  An older study showed just the opposite. A 2001 study in the International Journal of Cancer found evidence that smoking—even for those who gave up the habit—was associated with an increased risk of hormone-negative breast cancer.  In this long-term study, 10,902 women, 35 percent of whom were smokers, were followed for an average of 12.4 years. Those who smoked had an increased risk of hormone-negative breast cancer, but not of hormone-positive.  Ex-smokers specifically had an increased risk of progesterone-negative breast cancer.**

THE MORAL:  Don't smoke, because you don't want any kind of cancer.

---

*Kabat, Geoffrey C., Kim, Mimi, Phipps, Amanda I., Li, Christopher I., Messina, Catherine R., Wactawski-Wende, Jean, Kuller, Lewis, Simon, Michael S., Yasmeen, Shagufta, Wassertheil-Smoller, Sylvia  Rohan, Thomas E., ”Smoking and alcohol consumption in relation to risk of triple-negative breast cancer in a cohort of postmenopausal women.” Cancer Causes and Control : CCC , pp. 1-9 (2011).

** Manjer, J., Malina, J., Berglund, G., Bondeson, L., Garne, J. P.   Janzon, L., “Smokingassociated with hormone receptor negative breast cancer.” International Journal of Cancer, vol. 91, no. 4, 580-584 (2001).

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

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!