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Environmental Causes Of Triple Negative Breast Cancer

Epidermal Growth Factor Receptor

Risk factors for developing triple-negative breast cancer

The epidermal growth factor receptor is reported in 89% of TNBC and is considered an attractive therapeutic target, particularly in BL2 subtype tumors . The expression of this gene results in primary tumorigenesis and metastasis. The EGFR inhibitor gefitinib lowers the proliferation of cancer cells and increases carboplatin and docetaxel cytotoxicity . Several EGFR inhibitors, such as lapatinib and erlotinib, are currently being tested against TNBC, in addition to cetuximab and panitumumab . The synergistic therapeutic approach of monoclonal antibodies and chemotherapeutics is considered to be more effective. This can be exemplified by the combined use of carboplatin and cetuximab, and cisplatin and cetuximab proved to be more efficacious in patients with advanced TNBC . Additionally, tri-inhibitor therapy, including carboplatin, gefitinib, and docetaxel, enhances TNBC cytotoxicity. Cannabidiol inhibits breast cancer metastasis by interfering with the epidermal growth factor pathway . The epidermal growth factor receptor signaling pathway is presented along with activator and inhibitor points of action, as shown in Figure 2.

FIGURE 3. Inhibition of poly polymerase in BRCA-1/2-associated and sporadic cancers .

Where Do These Numbers Come From

The American Cancer Society relies on information from the Surveillance, Epidemiology, and End Results Program database, maintained by the National Cancer Institute , to provide survival statistics for different types of cancer.

The SEER database tracks 5-year relative survival rates for breast cancer in the United States, based on how far the cancer has spread. The SEER database, however, does not group cancers by AJCC TNM stages . Instead, it groups cancers into localized, regional, and distant stages:

  • Localized: There is no sign that the cancer has spread outside of the breast.
  • Regional: The cancer has spread outside the breast to nearby structures or lymph nodes.
  • Distant: The cancer has spread to distant parts of the body such as the lungs, liver, or bones.

Unique Features Of Immune Cells In Tnbc Microenvironment

TNBC accounts for 10%-20% of breast cancer and is the subtype with the worst prognosis. Various cell components in the TNBC microenvironment can be used as prognostic factors to predict the clinical results of TNBC and guide the treatment of TNBC. The tumor microenvironment consists of tumor cells and a variety of stromal cells, including tumor-related immune cells, fibroblasts and adipocytes. The microenvironment components and functions of different subtypes of breast cancer are different. For example, the cell infiltration rate of TILs and TAMs in the TNBC microenvironment is higher than that of other subtypes of breast cancer. In TNBC, M2-type macrophages are polymorphic in anti-inflammatory and stem cell renewal, and are significantly up-regulated compared with other subtypes of breast cancer. In addition, CAAs in TNBC microenvironment had a more significant effect on tumor cell growth and invasion .66,94

Table 1 The Main Cell Components in Microenvironment of Different Subtypes of Breast Cancer

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What Is A 5

A relative survival rate compares women with the same type and stage of breast cancer to women in the overall population. For example, if the 5-year relative survival rate for a specific stage of breast cancer is 90%, it means that women who have that cancer are, on average, about 90% as likely as women who dont have that cancer to live for at least 5 years after being diagnosed.

Symptoms Of Triple Negative Breast Cancer

Cancer cells force normal cells to secret virus like exosomes to help ...

The symptoms of triple negative breast cancer are similar to other breast cancer types.

Symptoms can include:

  • a new lump or thickening in your breast or armpit
  • a change in size, shape or feel of your breast
  • skin changes in the breast such as puckering, dimpling, a rash or redness of the skin
  • fluid leaking from the nipple in a woman who isnt pregnant or breast feeding
  • changes in the position of nipple

Make an appointment to see your GP if you notice anything different or unusual about the look and feel of your breasts.

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Orthotopic Mouse Model Of Breast Cancer

We conditioned MDA-MB-231 or Vari-068 cells as described above, harvested the cells with a cell dissociation buffer, and then injected 102, 103, or 104 MDA-MB-231 or 103 or 104 Vari-068 cells bilaterally into the fourth inguinal mammary fat of female NSG mice . We quantified tumor growth by caliper measurements in 3 dimensions and bioluminescence imaging at regular intervals as described previously . We defined experimental endpoints as time when FBS-conditioned tumors reached 1.0cm in diameter or 7080 days after implantation, whichever occurred first. At the endpoint, we measured tumor volume and visually inspected the organs for metastases. In select experiments, we removed organs and assessed the metastases by means of bioluminescence. We considered an organ positive for metastases if bioluminescence exceeded the background signal by at least 2-fold.

Why Is Triple Negative Breast Cancer Harder To Treat

Many of the most effective breast cancer treatments work by targeting receptors. For example, the drug trastuzumab kills breast cancer cells by latching onto the HER2 receptor, while tamoxifen works by blocking the oestrogen receptor and stopping oestrogen from stimulating breast cancer cells. Because triple negative cancers lack receptors, its not possible to treat them using targeted drugs like these.

Treatment for triple negative breast cancer is therefore limited to surgery, radiotherapy and chemotherapy. Because chemotherapy is not as targeted as drugs like trastuzumab and tamoxifen, it can cause significantly more side effects.

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What Is Triple Negative Breast Cancer

Triple negative breast cancer is a rare cancer that affects about 13 in 100,000 women each year. It represents about 15 % of all invasive breast cancers. Triple negative breast cancer is one of three types of breast cancer. It is called as triple negative because it doesnt have three markers associated with other types of breast cancer, which is important for prognosis and treatment. Its one of the more challenging breast cancers to treat. But researchers are making steady progress toward more effective treatments. Overall, 77% of women who have triple negative breast cancer are alive five years after diagnosis.

Targeting Tumor Microenvironment For Tnbc Therapy

Talk to Linda about Triple-Negative Breast Cancer

The development of TNBC has strong association with the physiological state of TME. TNBC has been characterized with unique TME and is different from other subtypes . TME has strong association with induction of angiogenesis, proliferation, apoptosis inhibition, suppression of immune system and resistance to drugs . The exosomes function as promising nanovesicles that directs TME orchestration by communicating cells within TME milieu . The different components of TME particularly the soluble factors, transformed extracellular matrix, immune suppressive cells, re-programmed fibroblasts and epigenetic modifications altogether helps in TNBC progression and metastasis . Hence, TME is regarded as a good therapeutic target. The different TME targets for therapeutic intervention is schematically presented in Figure 5.

FIGURE 5. Different TME targets for therapeutic intervention.

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What Is The Treatment For Triple

Chemotherapy.Chemotherapy is almost always called for, Sun says. Chemo can downstage tumors . While Sun says the chemotherapy for triple-negative breast cancer can be intense, she adds that regimen can be tailored to the individual and adjusted for older or frailer patients.

In those cases where we get complete response, we know we gave you the right medicine and your prognosis is good, Sun says.

Surgery can remove more of the tumor. Surgery for triple-negative breast cancer does not always have to be a mastectomy, Sun says. Effective chemotherapy done first opens up the possibility of less-invasive surgical options that are less of an ordeal for the patient. If the tumor is small enough after chemo, outpatient procedures or a lumpectomy may be possible.

Surgical samples of the cancerous tissues taken from surgery can provide more information on the cancer and how it is behaving so chemotherapy can be tailored accordingly.

Radiation therapy involves the use beams of radiation to destroy cancer cells, using various techniques to prevent damage to healthy surrounding tissue.

Medical treatments are being tested on triple-negative breast tumors in clinical trials.

Immunotherapy and PARP inhibitors are very exciting and theres lots of research going on, including here at Johns Hopkins, Sun says.

Some Household Detergents Antiseptics And Insecticides Are Potential Environmental Risk Factors And New Targets For Treating An Aggressive Form Of Breast Cancer Scientists Say

According to new data, exposure to common everyday chemicals may increase the risk of developing a difficult-to-treat type of breast cancer.

However, experts say that, while the study has no clinical or public health implications, it identifies areas for new research.

Triple negative breast cancer is an aggressive form that particularly affects younger people and makes up 10-20 per cent of all breast cancer diagnoses.

While curable if caught early, TNBC is resistant to hormone treatments and newer targeted therapies used to treat other types of breast cancer.

It is therefore treated with surgery, radiotherapy and chemotherapy.

Researchers say there is a better need to understand the biology of this aggressive form of breast cancer in order to develop new therapies, improve quality of life and identify how to reduce the risk of developing it.

Women with other types of breast cancer that are hormone receptor positive are treated with hormonal therapies which target oestrogen and progesterone receptors two of 48 nuclear receptors .

It is known that many NRs are altered in breast cancer. This means they can be potential drivers of breast cancer development and possible therapeutic targets.

The receptors act as environmental sensors, working together to control different aspects of how breast and other tissues work.

They mapped the entire NR superfamily in 68 breast cancer samples and from normal breast tissue, to identify common alterations in NR activity.

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Evidence Linking Environmental Factors And Breast Cancer

We turn now to the evidence addressing possible connections between exposures to environmental toxicants and risk for developing breast cancer. In exploring the scientific literature, we draw from relevant human, animal, cell-culture, and high throughput studies. Where possible, we address explicitly the complicating themes raised in the framing section above. And where appropriate, we present conflicting data, especially from the epidemiological literatures, that make clear the nuances of methodology and results that complicate these relationships.

What Is The Treatment For Triple Negative Breast Cancer


Healthcare providers and researchers are making significant progress on TNBC treatments. Recent clinical trials are testing new combinations of drugs and new approaches to existing treatments. Some existing treatments are:

  • Chemotherapy: Providers might combine chemotherapy and surgery, with chemotherapy being used to shrink your tumor before surgery or after surgery to kill cancer cells throughout your body.
  • Surgery: This could be a lumpectomy to remove an individual lump, or a mastectomy to remove an entire breast. Providers then perform a sentinel node biopsy or axillary node surgery to look for signs your breast cancer has spread to your lymph nodes.
  • Radiation therapy: Post-surgery radiation therapy helps reduce the chances your cancer will return or recur.
  • Immunotherapy: This treatment stimulates your immune system to produce more cancer-fighting cells or help healthy cells identify and attack cancer cells. Immunotherapy can be added to chemotherapy to before surgery to shrink the tumor. You might also receive immunotherapy for about a year after your surgery and post-surgery radiation therapy.

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How Effective Is Immunotherapy In Treating Triple

In stage 1 to 3 triple-negative breast cancer, immunotherapy is sometimes used to shrink a tumor before surgery.

In stage 4 breast cancer, immunotherapy is often combined with chemotherapy. For some people, adding immunotherapy to chemotherapy improves outcomes. A recent clinical trial studied immunotherapy treatment in women with advanced triple-negative breast cancer. In this trial, half of the group got chemotherapy, and the other half got both chemotherapy and immunotherapy. On average, it took longer for the cancer to progress in the people who got immunotherapy.

Immunotherapys side effects are different from those of other cancer medications. The most common ones are fatigue, rash, and diarrhea.

Immunosuppressive Immune Cells In The Tnbc Tumor Microenvironment

The tumor microenvironment involves the surrounding blood vessels, fibroblasts, immune cells, signaling molecules and the extracellular matrix around the tumor . Tumor Infiltrating Lymphocytes produce endogenous antitumor immune response for inhibiting tumor progression and improving free survival rate of TNBC patients . Tumor associated macrophages are important for immunosuppressive role by secreting inhibitory cytokines, regulatory T cells infiltration promotion, and reactive oxygen species reduction . Cancer-Associated Fibroblasts lower anti-tumor immunity, favor tumor cell proliferation and invasion and reshape the extracellular matrix . Tumor associated neutrophils aid in lysing tumor cells and induce antitumor function .

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What Are The Recurrence Rates

Although the response to chemos is appreciable, the chances of relapse of cancer in TNBC are disturbingly high. After initial treatment, some of the rogue cancerous cells escape the wrath of medications or therapies, travel down through the lymphatic system, and then there are chances of recurrence. There exist shreds of evidence that TNBC has a worse clinical outcome and a unique pattern of recurrence than other forms of breast cancers. After diagnosis, TNBC patients experience the highest chance of relapse of cancer within the first five years however, if the patient is cancer-free for that duration, the chances of cancer relapse lower down significantly.

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Is Breast Cancer Now Funding Research Into Triple Negative Breast Cancer

The breakthrough research giving hope to patients with triple negative breast cancer | 7NEWS

We have a dedicated Research Unit at Kings College London which is the only research unit in the UK focusing solely on understanding triple negative breast cancer and finding better ways to treat it.

Under the leadership of Professor Andrew Tutt, there are currently 29 researchers based at the unit, including Professor Ng and his team who study the role of immune cells in triple negative breast cancer. They are using imaging techniques to look at how immune cells enter the tumour environment and how this contributes to the growth and spread of triple negative breast cancer.

We also fund triple negative research elsewhere in the UK. For example, Professor Claire Lewis at the University of Sheffield is testing whether targeting two molecules called CXCR4 and VEGFA could prevent triple negative breast cancers from spreading around the body.

Dr Walid Khaled at the University of Cambridge is trying to understand how a protein called BCL11A, present in large amounts in triple negative breast cancer cells, is interacting with other proteins in these cells. He hopes that we may be able to kill triple negative breast cancer cells by using treatments to target these interactions.

Although this research may take some time to reach patients, its hoped these projects could lead to new treatment options for people with triple negative breast cancer.

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Characteristics Of Cafs In Tnbc

CAFs, the most common component of tumor stroma, especially in breast cancers, have been found to play a critical role in the breast tumor environment . The origin of CAFs is complex and debated. For example, CAFs may derive from resident fibroblasts, bone marrow-derived mesenchymal stem cells, hematopoietic stem cells, epithelial cells , and endothelial cells . They not only promote cancer initiation, progression, invasion, and metastasis but are also involved in series of microenvironmental events, including angiogenesis, ECM remodeling, the deposition of basement membrane components, cancer-associated inflammation and the regulation of differentiation events in associated epithelial cells, which are all known to be associated with cancer pathogenesis . A specific marker is necessary to detect CAFs in the tumor, and the most widely used such marker is -smooth muscle actin .

Tchou et al. were the first to show that CAFs derived from HER2+ breast cancers significantly augmented the invasive properties of the tumor cells via pathways associated with cancer cell migration, and these cells were more invasive than those from TNBC and ER-positive type cancers. Similar results were recently reported: high levels of all CAF-related proteins, such as platelet-derived growth factor receptor alpha , PDGFR and fibroblast activation protein alpha were reportedly associated with tumor invasiveness and more likely to be found in the HER-2 subtype than in TNBC .

What Makes Triple Negative Breast Cancer Worse Than Other Breast Cancers

Triple negative breast cancer tends to spread earlier and faster than other types of breast cancer. As TNBC is lacking the proteins that are targeted by hormonal and targeted therapies, the treatment options are more limited. Unfortunately, TNBC also has the highest likelihood of recurrence, or coming back, within the first 5 years after diagnosis. While advanced TNBC is still seen as an incurable disease, new treatment options, such as immunotherapy and PARP inhibitors, are starting to change this status quo.

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What Questions Should I Ask My Doctor

You will have lots of questions about your cancer, starting with your diagnosis. Here are some basic questions you might ask:

  • What is triple negative breast cancer?
  • How do you know my cancer is triple negative breast cancer?
  • Why did I get this cancer?
  • Do I need genetic testing?
  • Has my breast cancer spread, and if so, how far has it spread?
  • What is the stage of my cancer?
  • What is my prognosis or expected outcome?
  • What treatments do you recommend?
  • Why do you recommend those treatments?
  • What are those treatment side effects?
  • Will I need surgery? If so, what surgery do you recommend and why?
  • Im interested in participating in clinical trials. Are you able to help me find one?
  • Do you know if there are any local support groups?

A note from Cleveland Clinic

Triple negative breast cancer is one of the more challenging breast cancers to treat. You might be discouraged by what you have read about triple negative breast cancer. But there are a number of very effective treatments for triple negative breast cancer, including immunotherapy, chemotherapy, surgery and radiation. And every day researchers learn more about this rare cancer. Their knowledge is your power. If youre concerned you arent getting the straight story about your cancer, ask your healthcare provider to walk you through your diagnosis and treatment options.


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