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Feb 3, 2016 10:01PM
Mar 20, 2016 01:31PM
Thanks for starting this topic. I've been asking similar questions, but from a different angle.
How does estrogen affect the immune system within the realm of breast cancer?
This may be a tremendously important question to answer as the Oncology industry is shifting towards Immunotherapies and ER+ breast cancer has had a bad reputation of being "immunologically silent" (i.e. immune system doesn't see ER+ BC as foreign). That's probably why many early stage Immunotherapy clinical trials are focused on the triple negative (TNBC) population (as well as HER2+ patients).
A couple months back, I did some quick boolean searches on google for estrogen and the immune system.
I wanted to find the researchers who are looking to exploit Immunotherapy for hormone positive BC. Due to limited time, I didn't get far. However, I found studies done by Dr. Wael Jarjour who researches Immune system genes activated by estrogen causing autoimmune disorders like Lupus (SLE). That 2014 research is here: "Immune system genes activated by estrogen may hold clues to Lupus origin"
His lab website, here, essentially wrote:
"In investigating the role of estrogen receptors and estrogen in Systemic Lupus Erythematosus (SLE) and other autoimmune diseases, Dr. Jarjour of Ohio State demonstrated that estrogen up-regulates numerous genes that regulate the immune response. In 2013 publications, the team identified two novel targets of estrogen that are significantly up-regulated in SLE patients and play a critical role in regulating inflammation, specifically ZAS3 and TLR8. The research team is currently exploring functional consequences of this up-regulation".
I know this is not breast cancer related, but think about the statement: "estrogen up-regulates numerous genes that regulate the immune response."
Can this knowledge be leveraged and applied to breast cancer?
I may be grasping at straws, but I think regardless of steroidal status (ER or PR), the immune system has a bigger role in being able to fight breast cancer, despite those that still feel ER+ BC is not very immunogenic.
Where are the Labs conducting research on the connection between estrogen, breast cancer and the immune system?
To quote the The Emperor of All Maladies, "if cancer exploits the power of evolution to survive, perhaps only a commensurate weapon, equally adaptable, also perfected over millions of years, can overcome it. That weapon many scientists believe is the human immune system".
Immunotherapy drugs are the future for cancer therapy.
For those interested, here's the full article from Ohio-based Dr. Wael Jarjour:
Immune system genes activated by estrogen may hold clues to Lupus origin
Date: April 16, 2014
Source: Ohio State University Center for Clinical and Translational Science
Summary: Most autoimmune diseases disproportionately affect women, but scientists do not know why. Researchers say they've discovered a group of immune-regulating genes that increase activity in the presence of estrogen, which could help explain why women are better able to fight off infectious disease – and why they are more at risk for developing autoimmune diseases like lupus. The discovery also opens the door for new therapies that could help regulate estrogen's impact on these hormone-sensitive genes.
It's a phenomenon scientists observe whether they look at mortality rates in the United States, where medical care is relatively good, or third world nations, where medical care is often scarce: women are less likely to die from infectious diseases than men.
The lower death rate has been attributed to a beneficial, yet unexplained effect estrogen has on the immune system. However, some scientists also believe that estrogen may contribute to the development of autoimmune diseases, which overwhelmingly impact pre-menopausal women, causing debilitating and deadly symptoms.
"Estrogen appears to be a double-edged sword - on one side, protecting women from disease, on the other, potentially causing it," said Wael Jarjour, MD, director of The Ohio State University Wexner Medical Center's division of rheumatology and immunology. "However there isn't much research explaining how estrogen might have this duality, so it's a controversial theory."
Now, Jarjour and a team of immunology researchers at Ohio State and the University of Virginia (UVA) say they have some evidence to support that theory. They've discovered a group of immune regulating genes that become more active in the presence of estrogen, offering a clue to how the hormone's normally protective effects could go awry.
Jarjour and his team studied a family of immune response genes called toll-like receptors (TLRs), which are responsible for sending out chemical "danger signals" when a bacteria or virus is detected. These signals prompt a cascade of defenses designed to kill the pathogen; however, in a person with autoimmune disease, these inflammatory responses inexplicably turn against normal tissue. The team hypothesized that estrogen may stimulate TLR signaling, leading to a hyper-reactive immune state.
"When estrogen triggers these genes to become more active, the genes tell the immune system to get ready to fight," said Jarjour, whose lab is one of the few in the nation focusing on sex bias in auto-immune disease. "This 'standby' mode lowers the immune response threshold, which is helpful in fighting an infection, but could also set the stage for an autoimmune disease where the immune responses are out of control."
To test their theory, scientists triggered an immune response in cells from men and women with and without lupus -- an autoimmune disease that women are nine times more likely to get than men. Then, they added estrogen to see if gene activity changed, honing in on TLR8, an X chromosome-linked gene whose expression has already been implicated in the development of lupus.
The addition of estrogen boosted the level of immune response in all of the study samples, but the reactivity of cells from women was almost two times greater than that of cells from men.
"Clearly, estrogen regulates TLR8 and other TLRs in ways that change the threshold of an inflammatory response, and female cells are hard wired to be more sensitive to this change," said Nicholas Young, PhD, a molecular biologist with Ohio State's department of immunology who worked on the study.
Margaret Shupnik, PhD, a Professor of Medicine at UVA's School of Medicine who also worked with Jarjour's team says she hopes that the findings will prompt other researchers to develop novel therapies that regulate TLRs, and offer lupus patients the kind of treatment options that they currently don't have.
"There has been only one new lupus treatment introduced in the past 50 years, and our most powerful drugs shut down the immune system, causing difficult-to-manage side effects," noted Shupknik. "With evidence that TLR8 changes the way lupus patients respond to inflammation, therapies that regulate this protein might help prevent or treat this disease in ways that don't compromise the immune system."
The study on TLR8 was published in the March issue of Clinical Immunology. It is the second estrogen-regulated gene that Jarjour's team has discovered, and they are currently working on identifying several more. The researchers also plan on applying for a grant once they have compiled their findings on all genes in order to fully explore the estrogen-autoimmune disease connection.
"We have only just begun to appreciate the powerful and complex role estrogen plays in the immune system. More than 1,000 genes have estrogen receptor binding sites that control their expression, but less than one-tenth of those have been studied," noted Jarjour, who is also an associate professor of immunology at Ohio State's College of Medicine. "The overwhelming sex bias of autoimmune disease demands that the estrogen connection be studied more deeply."
Study enrollment of patients with and without lupus was supported by ResearchMatch, a service provided through the support of the Ohio State University Center for Clinical and Translational Science.
Systemic lupus erythematosus (SLE or lupus) is a chronic inflammatory autoimmune disease that impacts the entire body, but especially affects the skin, kidneys, lungs, blood, joints, brain and heart. Lupus is characterized by periods of activity (flares) and periods of remission. According to the Lupus Foundation of America, for most people with lupus, proper treatment can minimize symptoms, reduce inflammation and pain, and stop the development of serious organ damage. The disease can start at any age, but is most common in female minority populations, and 90 percent of people with lupus are women. It is estimated that 1.5 million people in the United States have lupus. The disease is more severe in children.
Wife was Age 45 at Dx 4/2014. BMX Surgery 6/2014 revealed: ILC, Stage 2 (Multifocal ILC, largest lesion 2.2 cm), Grade 2, ER+/PR+ (95%), HER2-, Ki-67 5-10%, Oncotype 11; Variant in the ATM gene
4/8/2014, ILC, Left, 2cm, Stage IIA, Grade 2, 0/3 nodes, ER+/PR+, HER2- (IHC)
6/26/2014 Mastectomy; Reconstruction (left); Reconstruction (right)