New Estrogen-Related Breast Cancer Mechanism Detected

Dr. Enrique Jacome

A previously unknown breast cancer-enabling mechanism has been discovered by researchers from the University of Illinois at Urbana-Champaign. The team's findings are published in the journal Oncogene.

The unfolded-protein response (UPR) pathway protects cells from stress and initiates the production of "chaperone proteins." These proteins fold and package other proteins, preparing cells to divide and grow. Because these chaperones are essential to the division of cells, they are now a popular target for cancer treatments.

"I like to think of this pathway as an assembly line," University of Illinois biochemistry professor David Shapiro explains. "In order for cells to divide, you're going to have to produce a lot more proteins. The chaperones help you to package, fold up and ship all these proteins."

Scientists know that the UPR is activated as part of astress response in scenarios when a cell is lacking oxygen or nutrients or is attacked by drugs. The activation of the UPR prepares the cell for growth, division and survival under stress.

The major new finding reported by the University of Illinois team is that the UPR is initiated by estrogen even before the emergence of any stresses associated with UPR activation.

Prof. Shapiro explains:

"This is a new role for estrogen in the pathology of cancer. Others have shown that stress activates this pathway, helping to protect some tumors. What is new is our finding that estrogen can pre-activate this pathway to protect tumors."

Prof. Shapiro and colleagues found the signal that activates the UPR pathway occurs when estrogen binds to its receptor, which causes a stockpile of calcium to flood into the cell. "It's also a signal that many researchers think has something to do with cell proliferation," says Prof. Shapiro. "The calcium itself may be a proliferation signal."

As well as protecting cells, though, the UPR can also trigger apoptosis - a kind of "cellular suicide" - in cases where a normal cell is exposed to too much stress. However, when the UPR is activated by estrogen, this cell-suicide response is "blunted," allowing cancer cells to survive and resist drugs.

UPR-related gene expression as prognostic marker

In another arm of the study, the researchers carried out a computer analysis of breast cancer data - investigating UPR-related gene expression - from women who had been diagnosed up to 15 years prior.

The results demonstrate that among women with estrogen-receptor-positive breast cancer who received tamoxifen as a treatment, those with "overexpressed" UPR were 3.7 times more likely to have breast cancer recurrence.

Looking at outcomes 10 years after diagnosis, 15% of women with the highest level of UPR-gene expression were cancer-free, compared with 80% of women with the lowest level of UPR expression.

Prof. Shapiro says the computer analysis shows that "UPR activation is a very powerful prognostic marker of the course of a woman's disease."

"Our marker helps identify breast cancers that are likely to be highly aggressive and therefore require intensive therapy," he adds.

Previous research has also found that UPR may contribute to sudden death in heart failure. In 2013, a study published in Circulation: Arrhythmia and Electrophysiology suggested that the UPR may explain the loss of many useful proteins that protect against heart failure.

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Study Shows Adding Chemotherapy To Radiation Treatment Not Effective In Treating Vulvar Cancer

Dr. Enrique Jacome

The addition of chemotherapy to post-surgical radiation treatment is not effective in treating vulvar cancer, according to Magee-Womens Hospital of UPMC research presented this week in San Francisco at the 56th annual meeting of the American Society for Radiation Oncology (ASTRO).

Vulvar cancer is extremely rare, accounting for just 4 percent of gynecologic cancers and 0.6 percent of cancers women face in the U.S. each year. Led by Sushil Beriwal, M.D., associate professor with the department of radiation oncology at the University of Pittsburgh School of Medicine and radiation oncologist at Magee, this study identified patients diagnosed with vulvar cancer between 1998 and 2011 who had undergone surgery to remove the cancer and required adjuvant radiation therapy because the disease had spread to their lymph nodes.

The study utilized the National Cancer Database, a nationwide oncology outcomes database, to identify 1,087 patients who underwent chemotherapy treatment in addition to radiation therapy after their initial surgery to remove the cancer. The study took into account factors including age, race, insurance coverage, tumor size and spread of the disease.

"Our study found that overall, the addition of chemotherapy to adjuvant radiation therapy did not improve patient survival," said Dr. Beriwal. "While retrospective studies do impose some limits on our conclusion, we found that at the very least, use of concurrent chemotherapy should be carefully evaluated on an individual basis."

While the study didn't confirm a benefit of the addition of adjuvant chemotherapy to treatment, Dr. Beriwal said it is important to share the findings because they move researchers one step closer to understanding how to most effectively treat vulvar cancer.

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Researchers Shed Light On How Breast Implants May Cause Rare Lymphoma

Dr. Enrique Jacome

Breast augmentation was the most commonly performed cosmetic surgical procedure in the US last year, with around 290,000 women receiving either silicone or saline breast implants. Although extremely rare, some patients who have had this procedure develop a blood cancer called anaplastic large cell lymphoma. Now, a new study has shed light on why this is.

Anaplastic large cell lymphoma (ALCL) is a rare type of non-Hodgkin lymphoma (NHL), responsible for around 3% of NHLs. ALCL typically appears in the skin, lymph nodes, liver and soft tissue.

On rare occasions, however, the cancer has appeared in the breast, and according to this latest research - led by Dr. Suzanne Turner of the University of Cambridge in the UK - almost all cases of breast ALCL have occurred in patients who have had breast augmentation, with the tumors always developing in the scar tissue surrounding the implant.

For their study, published in the journal Mutation Research, Dr. Turner and colleagues conducted a review of all available studies looking at ALCL, as well as patient case reports.

There have been 71 known ALCL cases worldwide that the researchers say are linked to the patient's breast implants. This shows that implant-related ALCL is extremely rare, affecting around 1-6 women in every 3 million who undergo breast augmentation.

But just because it is rare does not mean its underlying mechanisms should not be investigated, according to Dr. Matt Kaiser, head of research at Leukemia and Lymphoma Research in the UK - a blood cancer charity that funded the study:

"It is important to investigate any possible links to what causes these cancers, so that we can help people balance benefits versus risks and so that we can work out how we might be able to prevent the risks altogether."

Breast implants 'may trigger abnormal immune response, causing cancer'

Patients with ALCL are usually divided into two groups: those whose cancer cells possess an abnormal surface protein called anaplastic lymphoma kinase (ALK) and those whose cancer cells do not have ALK.

Patients with ALK-positive ALCL usually respond well to treatment and the majority survive 5 years or more, while those who are ALK-negative often require more aggressive treatment, with only around 50% surviving over 5 years.

However, Dr.Turner and her team found that nearly all patients included in their analysis with breast implant-related ALCL were ALK-negative, with most of them responding well to treatment. They note that of the 49 cases in which they had access to patients' treatment progress, only five deaths were reported.

Furthermore, they found that for many of these women, their cancer was successfully treated simply by removing their breast implant and the tissue surrounding it rather than undergoing chemotherapy or radiotherapy, indicating that the breast implant may trigger an abnormal immune response in the body, causing cancer.

These findings, the researchers say, provide clues to the underlying cause of breast implant-related ALCL and may pave the way for better treatment strategies specific to this disease. Dr. Turner says:

"It's becoming clear that implant-related ALCL is a distinct clinical entity in itself. There are still unanswered questions and only by getting to the bottom of this very rare disease will we be able to find alternative ways to treat it."

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The Sound Of A Ticking Clock Can Speed Up A Woman's Attitude On Reproductive Timing

Dr. Enrique Jacome

The metaphor of a ticking clock is often used to refer to a woman's growing urge - from puberty onwards to menopause - to conceive before her childbearing years are over. New research in Springer's journal Human Nature shows that there's more truth to this phrase than you might think. The subtle sound of a ticking clock can quite literally speed up a woman's reproductive timing. That is, the sound of a ticking clock can lead women to want to start a family at an earlier age, especially if she was raised in a lower socio-economic community. This is according to Justin Moss and Jon Maner of Florida State University in the US.

Reproductive timing refers to the time frame and the specific years during which people begin to focus their energy and resources towards bearing and caring for their offspring. Some researchers reason that when and how this happens is greatly influenced by a person's childhood years, his or her socio-economic background, and other subtle environmental factors.

Moss and Maner completed two experiments to test the influence of a subtle environmental factor - the ticking of a small white kitchen clock - on people's reproductive timing attitudes. In the first, 59 men and women were asked questions about the age at which they'd like to marry and start a family. It assessed how socio-economic background might influence some people to press the snooze button of their biological clocks, or begin to act. In the second experiment, the researchers examined to what extent 74 participants would alter the characteristics they normally sought in potential mates to possibly settle for less just in order to have children sooner.

Their findings suggest that priming the idea of the passage of time through the sound of a ticking clock can influence various aspects of women's reproductive timing. The effect was especially noticeable among women who grew up in lower socio-economic communities. They wanted to get married and have their first child at a younger age than women with more resources. They also lowered the priority that they placed on men's social status and long-term earning potential.

However, the effect of the clock did not do the same for men. The researchers were not surprised by this because men are able to father children well into their old age. Their reproductive lives are therefore not as limited as that of women.

"The very subtle sound prime of a ticking clock changed the timing with which women sought to have children and the traits they sought in potential partners - both central aspects of women's mating-related psychology," says Moss.

"The findings suggest that a woman's childhood years can interact with subtle environmental stimuli to affect her reproductive timing during adulthood," adds Maner.

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Semi-Soft Vaginal Drug-Delivery Suppository Could Limit The Spread Of HIV, AIDS

Dr. Enrique Jacome

A unique method for delivering compounds that could positively impact the global battle against HIV and AIDS may be possible, thanks to researchers in Penn State's College of Agricultural Sciences.

A semi-soft vaginal suppository made from the seaweed-derived food ingredient carrageenan and loaded with the antiviral drug Tenofovir provides a woman-initiated, drug-delivery vehicle that can protect against the spread of sexually transmitted infections during unprotected heterosexual intercourse, the researchers said.

With more than 34 million people worldwide living with HIV, microbicides - compounds that can be applied vaginally or rectally - offer a way to slow the spread of the virus, noted lead researcher Toral Zaveri, postdoctoral scholar in food science. Containing agents known to prevent transmission of HIV and other viruses, microbicides can be inserted into the vagina prior to intercourse as a gel, cream, foam, sponge, suppository or film.

Zaveri pointed out that carrageenan was selected over gelatin -- which traditionally has been used for semi-soft suppositories - because it offers a number of important advantages. Because carrageenan is plant based, it is acceptable to vegetarians, there is no risk of animal-acquired infections and it avoids religious objections. Also, it is more stable than gelatin at higher ambient temperatures common in tropical regions of the world.

The suppositories developed by the Penn State researchers hold particular promise for places such as regions of Africa, where HIV is widespread and women often are not in control of sexual situations, according to Zaveri. "Condoms have been successful in preventing transmission of HIV and other sexually transmitted infections. However, effectiveness depends on correct and consistent use by the male partner," she said. "Due to socioeconomic and gender inequities, women in some countries and cultures are not always in a position to negotiate regular condom use, so a drug-dispersing suppository can protect against transmission of HIV and other sexually transmitted infections during heterosexual intercourse with a partner whose infection status may or may not be known to the woman."

As part of the research, Zaveri, who earned her doctorate in biomedical engineering at the University of Florida, conducted extensive sensory-perception testing to assess acceptability of the suppositories among women. Women participating in the study at the Sensory Evaluation Center in Penn State's Department of Food Science were presented with suppositories - without the drug -- in a variety of sizes, shapes and textures. They indicated their preferences and rated the suppositories for willingness to try and imagined ease of insertion.

The initial evaluations all were done only in the hand as part of this preclinical development effort. Many factors go into making choices, Zaveri explained, such as vaginal products women may have used previously, as well as their sexual and cultural practices. Understanding women's perception of the suppository and reasons behind their choices is a critical step in the development of the suppository as a vaginal drug-delivery system.

Zaveri also studied the release of Tenofovir from the suppositories in a simulated vaginal environment to ensure that the drug will be released once inserted in the body, even in the presence of semen.

"Many people work on drug delivery and use different methods to create drug-delivery products, but not many focus on the end-user aspect of this," she said. "Obviously, the product can be effective only if it is acceptable to women and they use it. We have gone a step farther with this study to validate the acceptability of our suppositories among women - and that's critical. We are not just trying to make our product better, we also are trying to understand the reasoning behind the choices women make regarding vaginal drug delivery in general."

Zaveri noted that some may be surprised that biomedical research is done in the Department of Food Science. But she said it seemed natural given her collaboration on the study with Penn State faculty members Gregory Ziegler -- with recognized expertise in biopolymers such as carrageenan - and John Hayes, who is known for his proficiency in sensory-perception research on bitterness, oral burn and consumer acceptability.

"The biomedical use of a food additive - a material widely used in the food industry for its gelling, thickening and stabilizing properties - as a medium for a drug-delivery system is a novel idea, but we were playing to all of our strengths on the team," she said.

Previous microbicides were generally solids or liquids.

"We exploited the intermediate design space of viscoelastic materials known as gels," said Ziegler, "thus avoiding some of the drawbacks of these other dosage forms."

The real beauty of the concept, Zaveri suggested, is its potential for relatively quick commercialization because the material used to formulate the suppositories, carrageenan, is already approved, and safety studies have been done in previous microbicide clinical trials.

"Currently the suppositories are prepared in the lab by simple molding," she said. "However, the research team is investigating methods for large-scale production and packaging - key factors to be considered for product commercialization. Considering the safety, efficacy and user-acceptability tests that we are doing, it easily is possible for a company to take this product and run with it."

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