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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