3D structure of DNA is 'rewired' in hormone-resistant ER+ breast cancers

Epigenetic changes occur in the DNA of breast cancer cells that have developed a resistance to hormone therapy, an effective treatment for ER+ breast cancer, which accounts for 70% of all diagnoses.

Reversing these changes, researchers say, has significant potential to help reduce breast cancer relapse.

A team led by Professor Susan Clark at the Garvan Institute of Medical Research showed that the 3D structure of DNA is 'rewired' in hormone resistant ER+ breast cancers, altering which genes are activated and which genes are silenced in the cells. The researchers published the findings today in the journal Nature Communications.

"For the first time, we've revealed crucial 3D DNA interactions that are linked to whether or not a breast cancer is sensitive to hormone therapy," says senior author Professor Clark, who is Garvan's Genomics and Epigenetics Research Theme Leader. "Understanding this process reveals new insights into how ER+ cancers evade hormone therapy, allowing them to grow uncontrolled."

Tackling hormone resistance in breast cancer

The sex hormone estrogen can be an inadvertent driver of cancer growth - ER+ breast cancers grow when estrogen 'docks' to their cells. Treatment that blocks estrogen, known as hormone therapy, is successful at stopping cancer growth and reducing relapse, however many breast cancers become resistant to the treatment over time.

Treatment resistance is a significant health problem that leads to a third of all ER+ breast cancer patients on hormone therapy relapsing within 15 years."Dr Joanna Achinger-Kawecka, study's first author

We are interested in epigenetic changes to DNA, the layer of instructions that organizes and regulates DNA's activity, that underpin the development of hormone resistance in breast cancer. Understanding these fundamental changes may help guide development of future treatments that either prevent resistance from developing, or reverse it once it has occurred."

Uncovering hidden changes to DNA

Using chromosome conformation capture, a cutting-edge technique that provides a snapshot of how DNA is arranged and interacts in three dimensions in the cell, the researchers compared different ER+ breast cancer cells that were either sensitive or resistant to hormone treatment.

"Between breast cancer cells that were still sensitive to hormone treatment and those that had developed resistance, we saw significant changes in 3D interactions of DNA regions that control gene activation. Including at genes that control the estrogen receptor levels in the cells," says Dr Achinger-Kawecka.

"Further, we found that this 3D 'rewiring' occurred at DNA regions that were methylated, which is an epigenetic change that the team has already linked to hormone resistance."

The researchers say that the altered DNA methylation at critical regulatory regions may explain how the 3D structure of DNA is rewired as a cancer cell develops hormone resistance, allowing the cancer to better evade treatment.

A new path for breast cancer treatment

"Cancer cells are always trying to outsmart therapy and it only takes one cell to evolve a different way to bypass a drug to cause a relapse in cancer," says Professor Clark. "Our study shows us just how much impact a change in the epigenome can have on cancer cell behavior."

The researchers say the next step is to investigate whether epigenetic changes could be reversed to stop hormone resistance, using existing drugs that are already in clinical trials for other cancers, including lung and colorectal cancer.

"Once ER+ breast cancer patients become resistant to hormone therapy, it is more difficult to treat," says Professor Clark. "We hope our research will help lead to combination treatments that allow women to take hormone therapy for longer, giving them better clinical outcomes."

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Scientist Destroyed Breast Cancer Tumours in Days Without Chemo

Research revealed that scientists had tested the effectiveness of a pair of drugs- known as Herceptin- a.k.a. trastuzumab, and Lapatinib.

The two drugs are commonly used in breast cancer treatment already, but this is the first time they had been combined together and used before surgery and chemotherapy. What they found was they're able to eliminate some types of breast cancer in just 11 days.

The scientists aimed to use these drugs to combat a protein called HER2( human epidermal growth receptor 2) which affects the growth and division of cancer cells. It's also more likely to return than other cancer types.

What also makes this treatment so appealing is the fact that it eliminates the need for chemotherapy and surgery. The temporary effects like hair loss, vomiting and fatigue are also avoided, making this treatment less impactful on the body. Chemotherapy is not entirely effective, nor is it the right choice for a lot of patients, so any alternatives are welcomed.

Research results
257 women with HER2 positive breast cancer were selected for the study, with half being out on drug combo and the other half were the control group. What they found was that those on the drug ,11% had no cancer cells remaining two weeks and 17% of the cases had dramatically shrunken tumours.

Compared to the control group who were only given Hereptin, they're found to have 0% with no trace of cancer cells and only 3 % showed a drop in tumour size. Clearly the two drugs combined have a major effect on breast cancer cells as opposed to being used on their own.

The problem currently however, is that Herceptin's licensing makes it available for use alongside chemo and not alone. The results of this study may help to change that view.

Although, there is still a lot of work to be done, hopefully, this is a major step in the fight against one of the world's deadliest diseases. With medical advancements improving every year, it's entirely possible this could happen sooner than we think.

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Researchers Successfully Turn Breast Cancer Cells Into Fat to Stop Them From Spreading

Researchers have been able to coax human breast cancer cells to turn into fat cells in a new proof-of-concept study in mice.

To achieve this feat, the team exploited a weird pathway that metastasising cancer cells have; their results are just a first step, but it's a truly promising approach.

When you cut your finger, or when a foetus grows organs, the epithelium cells begin to look less like themselves, and more 'fluid' – changing into a type of stem cell called a mesenchyme and then reforming into whatever cells the body needs.

This process is called epithelial-mesenchymal transition (EMT) and it's been known for a while that cancer can use both this one and the opposite pathway called MET (mesenchymal‐to‐epithelial transition), to spread throughout the body and metastasise.

The researchers took mice implanted with an aggressive form of human breast cancer, and treated them with both a diabetic drug called rosiglitazone and a cancer treatment called trametinib.

Thanks to these drugs, when cancer cells used one of the above-mentioned transition pathways, instead of spreading they changed from cancer into fat cells – a process called adipogenesis.

"The models used in this study have allowed the evaluation of disseminating cancer cell adipogenesis in the immediate tumour surroundings," the team writes in their paper.

"The results indicate that in a patient-relevant setting combined therapy with rosiglitazone and trametinib specifically targets cancer cells with increased plasticity and induces their adipogenesis."

Although not every cancer cell changed into a fat cell, the ones that underwent adipogenesis didn't change back.

"The breast cancer cells that underwent an EMT not only differentiated into fat cells, but also completely stopped proliferating," says senior author of the study.

"As far as we can tell from long-term culture experiments, the cancer cells-turned-fat cells remain fat cells and do not revert back to breast cancer cells."

So how does this work? Well, as a drug trametinib both increases the transition process of cells - such as cancer cells turning into stem cells - and then increases the conversion of those stem cells into fat cells.

Rosiglitazone was less important, but in combination with trametinib, it also helped the stem cells convert into fat cells.

"Adipogenic differentiation therapy with a combination of rosiglitazone and [trametinib] efficiently inhibits cancer cell invasion, dissemination, and metastasis formation in various preclinical mouse models of breast cancer," the team said.



 The image above shows this process, with the cancer cells tagged with a green fluorescent protein and normal red fat cell on the left. The cancer-turned-fat cells display as brown (on the right) because the red of the fat cells combines with the green of the protein cancer cell tag.

What's exciting is that these two drugs are already FDA-approved, so it should be easier to get this type of treatment into clinical trials for actual people.
 
That's exciting even despite the fact that we know many mouse-tested treatments don't actually make it to, or fail, the clinical trial stage. The fact this worked on human cancer cells gives a little extra hope.

In the meantime, the team is investigating whether this therapy would work combined with chemotherapy, and whether it would apply to other types of cancers.

"In future, this innovative therapeutic approach could be used in combination with conventional chemotherapy to suppress both primary tumour growth and the formation of deadly metastases," the author said.

"The clinical evaluation of the treatment's repressive effect on experimental breast cancer metastasis and, thus, of its potential in treating stage IV breast cancer will require adjuvant combinations with chemotherapy in advanced preclinical models," the researchers said.

"Since we have used FDA-approved drugs to study the preclinical effect of the treatment, a clinical translation may be possible."

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EIGHT WONDERFUL SPICES WHICH BOOST HEALTH

Modern science is beginning to uncover the ultimate power of spices and herbs- as weapons against illnesses, from cancer to Alzheimer's disease.
While science has yet to show that any spice cures disease, there's compelling evidence that several of them may help manage some chronic conditions.
And of course, seasoning your dishes with spices allows you to use less of other ingredients linked with health problems, such as salt, added sugars and sources of saturated fat.

8 of the world's healthiest spices and herbs.

1. Sage- to preserve memory, soothe sore throats.
Today's herbalists recommend sipping sage tea for upset stomachs and sore throats. One study found that spraying sore throats with a sage solution gave effective pain relief. Whoever gave the herb the wisdom-connoting " sage" moniker may have been onto something preliminary research suggests the herb may improve some symptoms of early Alzheimer's disease by preventing a key enzyme from destroying acetylcholine, a brain chemical involved in memory and learning.

2. Parsley- to prevent cancer. 
University of Missouri scientists found that this herb can actually inhibit breast cancer cell growth.
Animals that were given apigenin, a compound abundant in parsley( and in celery), boosted their resistance to developing cancerous tumours.
Experts recommend adding a couple of pinches of minced fresh parsley to your dishes daily.

3. Turmeric- to quell inflammation, inhibit tumours. In India, turmeric paste is applied to wounds to speed up healing, People sip turmeric tea to relieve colds and respiratory problems. Modern science confirms some surefire health benefits as well- most are associated with curcumin, a compound in turmeric that has potent antioxidant and anti-inflammatory properties. Curcumin has been shown to relieve pain of arthritis, injuries and dental procedures. It's also being studies for its potential in managing heart disease, diabetes and Alzheimer's disease.

4. Ginger- to soothe an upset stomach, fight arthritis pain. Traditionally used to relieve colds and stomach troubles, ginger is rich in inflammation-fighting compounds, such as gingerols, which some experts believe may hold promise in fighting some cancers and reducing arthritis pain. In recent study, people who took ginger capsules daily for 11 days reported 25 % less muscle pain when they performed exercise designed to strain their muscles ( compared with a similar group taking placebo capsules).
Another study found that ginger extract injections helped relieve osteoarthritis pain in the knees. In addition, ginger's reputation as a stomach-soother seems deserved-studies show ginger extracts can help reduce nausea caused by morning sickness or following surgery or chemotherapy, though it's less effective for motion sickness.

5. Cinnamon- to stabilize blood sugar. Cinnamon was prized by King Solomon and used by the ancient Greeks and Romans to boost appetite and relieve indigestion.
A few studies suggest that adding cinnamon to food-up to a teaspoon a day usually administered in capsule form-might help people with type 2 diabetes to better control their blood sugar, by lowering post-meal blood sugar spikes. Other studies suggest the effects are limited at best.

6. Chillipepper- to boost metabolism.
Chilies, which create sensations of heat ranging from mild to fiery, are especially prized in hot climates since, ironically, the spice helps trigger the body's natural cooling system.
Studies show that capsaicin- a pngent compound in hot chilies- kick-starts the body's metabolism and may boost fat burning, but the jury is still out on whether that translates to long-term weight loss.
Recent research found that capsinoids, similar but gentler chemicals found in milder chili hybrids, have the same effects, so even tamer sweet paprika packs a healthy punch.

7. Saffron- to boost your mood, relieve symptoms of PMS.
Saffron has long been used in traditional Persian medicine as a mood lifter, usually steepd into a medicinal tea or used to prepare rice.
Research from Iran's Roozbeh Psychiatric Hospital at Tehran University of Medical Sciences has found that saffron may help to relieve symptoms of pre-menstrual syndrome (PMS) and depression.
In one study, 75% of women with PMS who were given saffron capsules daily reported that their PMS symptoms ( such as mood swings and depression) declined by at least half, compared with only 8% of women who didn't take saffron.

8. Rosemary- to enhance mental focus and fight foodborne bacteria.
In ancient Greece, scholars wore rosemary garlands to help them study, and one recent study found that people performed better on memory and alertness thests when mists of aromatic rosemary oil were piped into their study cubicles.
Rosemary os often used in marinades for meats and poultry, and there's scientific wisdom behind that traditin: Rosmarinic acid and other antioxidant compounds in the herb fight bacteria and prevent meat from spoiling, and may even make cooked meats healthier.
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Compound In Broccoli Slows Cancer Cell Growth

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 A compound found in broccoli and other cruciferous vegetables has been found to slow the growth of breast cancer cells, especially at early stages.

While sulforaphane has long shown evidence of value in cancer prevention, researchers at Oregon State University (OSU) and the Oregon Health and Science University suggested in a new study that it may play a role in slowing cancer growth as well, Xinhua reported.

The findings were the result of the first clinical studies to look at the effect of sulforaphane on breast tissues of women diagnosed with breast cancer.

Emily Ho, a professor at the OSU College of Public Health and Human Sciences, said: "Our original goal was to determine if sulforaphane supplements would be well tolerated and might alter some of the epigenetic mechanisms involved in cancer."

In a double-blind, randomised, placebo-controlled trial, 54 women with abnormal mammograms were given either a placebo or supplements that provided sulforaphane. The amount of sulforaphane they received would equate to about one cup of broccoli sprouts per day, if eaten as a food.

"We were surprised to see a decrease in markers of cell growth, which means these compounds may help slow cancer cell growth," said Ms Ho.

"This is very encouraging. Dietary approaches have traditionally been thought to be limited to cancer prevention, but this demonstrated it could help slow the growth of existing tumours," she said.

Previous studies have found that women with a high intake of cruciferous vegetables, such as broccoli, cauliflower, cabbage or kale, have a decreased risk of breast cancer. In particular, sulforaphane appears to inhibit histone deacetylases, or HDACs, which in turn enhances the expression of tumour suppressor genes that are often silenced in cancer cells.

In the new study published in the journal Cancer Prevention Research, the intake of sulforaphane did reduce HDAC activity, as well as cancer cell growth.

As co-author of the study, Ho said it is possible that sulforaphane may be added to traditional approaches to cancer therapy, whether to prevent cancer, slow its progression, treat it or stop its recurrence.

Researchers said additional studies are needed to evaluate dose responses, work with larger populations, and examine the responses of other relevant molecular targets to either foods or supplements containing sulforaphane.