Breast Cancer Spreads to brain By Disguising Itself as Brain Cells

Often, several years can pass between the time a breast cancer patient successfully goes into remission and a related brain tumor develops. During that time, the breast cancer cells somehow hide, escaping detection as they grow and develop.

Breast cancer cells disguise themselves as neurons, becoming “cellular chameleons,” found the scientists from City of Hope in Duarte, California. This allows them to slip undetected into the brain and then develop into tumors. The discovery is being heralded as “a tremendous advance in breast cancer research.”

Although breast cancer is a very curable disease—with more than 95% of women with early-stage disease surviving after 5 years—breast cancer that metastasizes to the brain is difficult to fight. Only about 20% of patients survive 1 year after diagnosis.

“There remains a paucity of public awareness about cancer’s relentless endgame,” said Rahul Jandial, MD, PhD, a City of Hope neurosurgeon who headed the breast-cancer-and-brain-tumor study, published in the Proceedings of the National Academy of Sciences (2014; doi:10.1073/pnas.1322098111). “Cancer kills by spreading. In fact, 90% of all cancer mortality is from metastasis,” Jandial said. “The most dreaded location for cancer to spread is the brain. As we have become better at keeping cancer at bay with drugs such as herceptin, women are fortunately living longer. In this hard-fought life extension, brain metastases are being unmasked as the next battleground for extending the lives of women with breast cancer.”

He added, “I have personally seen my neurosurgery clinic undergo a sharp rise in women with brain metastases years—and even decades—after their initial diagnosis.”

Jandial and other scientists wanted to explore how breast cancer cells cross the blood-brain barrier—a separation of the blood circulating in the body from fluid in the brain—without being destroyed by the immune system.

The researchers’ hypothesis was that,  given that the brain is rich in many brain-specific types of chemicals and proteins, perhaps breast cancer cells that could exploit these resources by assuming similar properties would be the most likely to flourish. These cancer cells could deceive the immune system by blending in with the neurons, neurotransmitters, other types of proteins, cells, and chemicals.

Taking samples from brain tumors resulting from breast cancer, the scientists found that the breast cancer cells were exploiting the brain’s most abundant chemical as a fuel source. This chemical, gamma-aminobutyric acid (GABA), is a neurotransmitter used for communication between neurons.

When compared with cells from nonmetastatic breast cancer, the metastasized cells expressed a receptor for GABA, as well as for a protein that draws the transmitter into cells. This allowed the cancer cells to essentially masquerade as neurons.

“Breast cancer cells can be cellular chameleons (or masquerade as neurons) and spread to the brain,” Jandial said.

He added that further study is required to better understand the mechanisms that allow the cancer cells to achieve this disguise, and he hopes that, ultimately, unmasking these disguised invaders will result in new therapies.

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Body Fat Distribution and ER-negative Breast Cancer

What scientists call "Overweight" ch...
Photo credit: Wikipedia

Body fat distribution does not play an important role in the incidence of every subtype of premenopausal breast cancer, but is associated with an increased risk for estrogen receptor (ER)-negative breast cancer, according to a study published December 15 in The Journal of the National Cancer Institute. abdominal adiposity, or waist circumference and the waist to hip ratio, was more strongly associated with risk of ER-negative breast cancer than with the risk of ER-positive breast cancer. The researchers found no statistically significant associations between waist circumference, hip circumference, or the waist to hip ratio and overall risk of breast cancer.

“These findings may suggest that an insulin-related pathway of abdominal adiposity is involved in the etiology of premenopausal breast cancer,” the authors write.

Study Details: Previous studies have shown that the association between body mass index (BMI) and the risk of breast cancer varies with menopausal status: a higher BMI is positively associated with risk of postmenopausal breast cancer but inversely associated with risk of premenopausal breast cancer. Intra-abdominal fat that surrounds organs has been associated with metabolic and hormonal changes that have been associated with premenopausal breast cancer risk, although prospective studies have produced conflicting results, and none have examined the role of hormone receptor status.

To determine the relation between body fat distribution and premenopausal breast cancer risk, Holly R. Harris, Sc.D., of Brigham and Women’s Hospital and Harvard Medical School in Boston, and colleagues, conducted a prospective analysis among women in the Nurses’ Health Study II, a cohort of 116,430 women who have been followed up since 1989. In 1993 the researchers sent women in that study a questionnaire in which the women were asked to measure and report their waist and hip circumference.

I’m Dr. Michael Hunter.

The small print: The material presented herein is informational only, and is not designed to provide specific guidance for an individual. Please check with a valued health care provider with any questions or concerns. As for me, I am a Harvard- , Yale- and UPenn-educated radiation oncologist, and I practice in the Seattle, WA (USA) area. I feel genuinely privileged to be able to share with you. If you enjoyed today’s offering, please consider clicking the follow button at the bottom of this page.

Available now: Understand Colon Cancer in 60 Minutes; Understand Brain Glioma in 60 Minutes. Both can be found at the Apple Ibooks store. Coming Soon for iPad:  Understand Breast Cancer in 60 Minutes; Understand Colon Cancer in 60 Minute; Understand Colon Cancer in 60 Minutes; Understand Brain Glioma in 60 Minutes. Thank you.

Reference: Journal of the National Cancer Institute (2010, December 15). Body fat distribution associated with a higher risk of ER-negative breast cancer. ScienceDaily. Retrieved November 28, 2013, from http://www.sciencedaily.com­/releases/2010/12/101215163742.htm

Trigger for Breast Cancer Metastasis Identified

A diagram showing a mitochondrion of the eukar...
Mitochondria are organelles surrounded by membranes, distributed in the cytosol (liquid part) of most eukaryotic cells. Its main function is the conversion of potential energy of pyruvate molecules into ATP, molecule that act as fuel for the cell. (Photo credit: Wikipedia)

For years, scientists have observed that cancer cells from certain breast cancer patients (with aggressive forms of the disease) contained low levels of mitochondrial DNA. No one could explain how this characteristic influenced disease progression. Until now.

The Science: Mitochondria, the “powerhouses” of mammalian cells, are also a signaling hub. They are heavily involved in cellular metabolism as well as in apoptosis, the process of programmed cell death by which potentially cancerous cells can be killed before they multiply and spread. In addition, mitochondria contain their own genomes, which code for specific proteins and are expressed in coordination with nuclear DNA to regulate the provision of energy to cells.

In mammals, each cell contains between 100 and 1,000 copies of mitochondrial DNA, but previous research had found that as many as 80 percent of people with breast cancer have low mitochondrial DNA, or mtDNA, content.

What The Researchers Did: To gain an understanding of the mechanism that connects low mtDNA levels with a cellular change that leads to cancer and metastasis, the investigators set up two systems by which they could purposefully reduce the amount of mtDNA in a cell. One used a chemical to deplete the DNA content, and another altered mtDNA levels genetically. They compared normal, non-cancer-forming human breast tissue cells with cancerous breast cells using both of these treatments, contrasting them with cells with unmanipulated mtDNA.

The differences between cells with unmodified and reduced mtDNA levels were striking, the researchers found. The cells in which mtDNA was reduced had altered metabolism and their structure appeared disorganized, more like that of a metastatic cancer cell. Even the non-tumor-forming breast cells became invasive and more closely resembled cancer cells. Significantly, cells with reduced mtDNA became self-renewing and expressed specific cell surface markers characteristic of breast cancer stem cells.

“Reducing mitochondrial DNA makes mammary cells look like cancerous stem cells,” Avadhani said. “These cells acquire the characteristics of stem cells, that is the ability to propagate and migrate, in order to begin the process of metastasis and move to distal sites in the body.”

“Most patients who had low copy numbers of mitochondrial DNA have a poordisease prognosis,” Guha said. “We’ve shown a causal role for this mitochondrial defect and identified a candidate biomarker for aggressive forms of the disease. In the future, mtDNA and the factors involved in mitochondrial signaling may serve as markers of metastatic potential and novel points for therapeutic intervention of cancer stem cells. Since the specific inducers of cancer stem cells, which are key drivers of metastasis, remain elusive, our current findings are a significant advancement in this area.”

No two breast cancers are exactly alike, so having a way to recognize patients who are at high-risk for developing particularly invasive and rapidly metastasizing cancers could help physicians customize treatments. In addition, researchers are currently filling in the unknown components of the signaling pathway linking a cell’s mitochondrial DNA levels and its involvement in metastatic disease.

Researchers will move to mouse models, and to ways of finding how we can use this seemingly key information for humans. I’m Dr. Michael Hunter.

The small print: The material presented herein is informational only, and is not designed to provide specific guidance for an individual. Please check with a valued health care provider with any questions or concerns. As for me, I am a Harvard- , Yale- and UPenn-educated radiation oncologist, and I practice in the Seattle, WA (USA) area. I feel genuinely privileged to be able to share with you. If you enjoyed today’s offering, please consider clicking the follow button at the bottom of this page.

Available now: Understand Colon Cancer in 60 Minutes; Understand Brain Glioma in 60 Minutes. Both can be found at the Apple Ibooks store. Coming Soon for iPad:  Understand Breast Cancer in 60 Minutes; Understand Colon Cancer in 60 Minute; Understand Colon Cancer in 60 Minutes; Understand Brain Glioma in 60 Minutes. Thank you.

References: 1. http://www.sciencedaily.com/releases/2013/11/131108124850.htm; 2. M Guha, S Srinivasan, G Ruthel, A K Kashina, R P Carstens, A Mendoza, C Khanna, T Van Winkle, N G Avadhani. Mitochondrial retrograde signaling induces epithelial–mesenchymal transition and generates breast cancer stem cells. Oncogene, 2013; DOI: 10.1038/onc.2013.467

Adjuvant Radiotherapy in Older Women with Early Breast Cancer: Benefits Questioned

older senior elderly woman doctor

Summary: Adding radiation therapy to tamoxifen after lumpectomy was associated with modestly lower risk ofr local and regional recurrence, but no survival advantage.

The Study: CALGB 9343 was a trial designed to evaluate lumpectomy plus tamoxifen with or without breast radiation therapy. Patients were at least 70 years old, had Stage I disease, and tumors that were hormone receptor positive. The trial was conducted from 1994 to 1999.

Results: At a median follow-up 12.6 years, the benefit of whole breast radiation therapy was statistically significant: At 10 years, 98% of patients who received tamoxifen plus radiation therapy were free from local-regional recurrences, compared with 90% of those who received only tamoxifen. However, mastectomy rates, distant metastases, overall survival, and risk of second primary cancers or death from other causes did not differ when comparing the two groups.

My Take: The current US National Comprehensive Cancer Network Guidelines state that radiation therapy after lumpectomy can be omitted in women 70 or older who have estrogen receptor-positive, node-negative breast cancers that are less than 2cm in size, and who receive adjuvant endocrine therapy. I agree, but I would offer radiation therapy to those women who want to optimize local control, who have few medical co-morbidities, and a high probability of surviving at least 10 years. And I would also in general be more aggressive with more advanced stage disease. I’m Dr. Michael Hunter, and I thank you for letting me share my thoughts.

The small print: The material presented herein is informational only, and is not designed to provide specific guidance for an individual. Please check with a valued health care provider with any questions or concerns. As for me, I am a Harvard- , Yale- and UPenn-educated radiation oncologist, and I practice in the Seattle, WA (USA) area. I feel genuinely privileged to be able to share with you. If you enjoyed today’s offering, please consider clicking the follow button at the bottom of this page.

Available now: Understand Colon Cancer in 60 Minutes; Understand Brain Glioma in 60 Minutes. Both can be found at the Apple Ibooks store. Coming Soon for iPad:  Understand Breast Cancer in 60 Minutes; Understand Colon Cancer in 60 Minutes, available now: Understand Colon Cancer in 60 Minutes; Understand Brain Glioma in 60 Minutes. Thank you.

Reference: Hughes KS et al. Lumpectomy plus tamoxifen with or without irradiation in women age 70 years or older with early breast cancer: Long-term follow-up of CALGB 9343.J Clin Oncol 2013 Jul 1; 31:2382.

Breast Augmentation: Should We Discuss Impact on Cancer Detection?

stk212573rkeBreast augmentation continues to be the most popular form of plastic surgery, according to the American Society of Plastic Surgeons. Now comes a systematic review and meta-analysis (study of studies), published online on April 30 in the British Medical Journal that concludes cosmetic breast augmentation lowers the survival of women who are subsequently diagnosed with breast cancer.

My take: Breast implants can obscure mammogram images, which can decrease the ability of mammograms to find breast cancer. Still, mammograms are an effective way to screen for breast cancer, as a diagnostic examination, in women with breast implants. In addition, the results of the study are not definitive: Flaws include the fact that only a small number (12) of studies were evaluated. Of these, only 5 looked at survival. And many other studies (including some large, controlled ones conducted in the USA) have not found worse detection among those with implants.

Additional images should be added to the standard mammogram when implanted women have imaging. With additional implant displacement views (Eklund views), the screening examination becomes a diagnostic mammogram. These views can help visualize  breast tissue, although in any mammogram there is a certain amount of obscuring of the breast tissue because of the implant. If you have implants, you should find a facility that sees many women with breast implants and is familiar with interpreting these mammogram images. Digital mammography may also aid with visualization of breast tissue because the images can be enlarged and manipulated to a certain extent. I’m Dr. Michael Hunter.

The small print: The material presented herein is informational only, and is not designed to provide specific guidance for an individual. Please check with a valued health care provider with any questions or concerns. As for me, I am a Harvard- , Yale- and UPenn-educated radiation oncologist, and I practice in the Seattle, WA (USA) area. I feel genuinely privileged to be able to share with you. If you enjoyed today’s offering, please consider clicking the follow button at the bottom of this page.

Available now: Understand Colon Cancer in 60 Minutes; Understand Brain Glioma in 60 Minutes. Both can be found at the Apple Ibooks store. Coming Soon for iPad:  Understand Breast Cancer in 60 Minutes; Understand Colon Cancer in 60 Minuteable now: Understand Colon Cancer in 60 Minutes; Understand Brain Glioma in 60 Minutes. Thank you.