Summary: Researchers have discovered the mechanism behind the development of brain metastases in women with HER2-positive breast cancer.
Source: City of Hope.
Breast cancer cells express brain proteins to avoid natural defenses.
Ninety percent of cancer deaths are from cancer spread. Breast cancer patients, for example, typically do not die because cancer returns in their breast, they die because it spreads to other parts of their body. The most dangerous of which is the brain. Approximately 40 percent of all women with HER2-positive breast cancer will develop brain metastases. Now City of Hope researchers have found how this happens.
Breast cancer cells wrap themselves in reelin — a protein typically found only in the brain — that allows the cells to disguise themselves as “friend and not foe,” avoiding a system in the brain designed to detect enemy cells. From these disguised cells, new deadly brain tumors form.
“More women than ever are surviving breast cancer only to die from breast tumors growing in their brains years after they’ve been declared cancer-free,” said City of Hope dual trained neurosurgeon and scientist Rahul Jandial, M.D., Ph.D., who led the study available online and slated for the upcoming print publication of the Clinical & Experimental Metastasis, the journal for the Metastases Research Society. “I wanted to understand why women with HER2-positive breast cancer (around 20 percent of all breast cancers) have higher rates of brain metastases than women with other breast cancer subtypes and in turn, find their biological Achilles heel to develop new medicines.”
After performing brain surgery, Jandial and his team took leftover tissue samples and compared them to breast cancer tissue removed from mastectomies in the same women. They compared the expression of proteins and found that reelin expression was low in primary breast cancer tissue. However, its expression was significantly higher in HER2-positive breast cancer metastasizing to the brain.
“The cells are essentially able to act as spies that look like citizens,” said Jandial. “They release a mesh of protein and escape the brain’s natural defense weapons, causing tumors to grow in the brain.”
Understanding these mechanisms is an important step in developing new therapies to treat brain cancers — especially for metastatic cancers. Metastases are responsible for 90 percent of all cancer deaths, and patients diagnosed with brain metastases only have a 20 percent chance of surviving a year after diagnosis.
Collaborating authors include Cecilia Choy, Ph.D., Danielle M. Levy, Ph.D., Mike Y. Chen, M.D., Ph.D. and Khairul I. Ansari, Ph.D., all of Beckman Research institute of City of Hope.
Funding: Funding for this research is supported by Department of Defense Grant BC142323, The Margaret E. Early Medical Research Trust, National Institutes of Health Grant K12 CA001927-16A1 and National Cancer Institute Grant P30 CA033572.
Source: Denise Heady – City of Hope
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: Full open access research for “Astrocyte-induced Reelin expression drives proliferation of Her2+ breast cancer metastases” by Rahul Jandial, Cecilia Choy, Danielle M Levy, Mike Y Chen, and Khairul I Ansari in Clinical & Experimental Metastasis Journal. Published online February 17 2017 doi:10.1007/s10585-017-9839-9
Astrocyte-induced Reelin expression drives proliferation of Her2+ breast cancer metastases
Breast cancer metastasis to the brain develops after a clinical latency of years to even decades, suggesting that colonization of the brain is the most challenging step of the metastatic cascade. However, the underlying mechanisms used by breast cancer cells to successfully colonize the brain’s microenvironment remain elusive. Reelin is an archetypal extracellular glycoprotein that regulates migration, proliferation, and lamination of neurons. It is epigenetically silenced in various cancers, and its expression in multiple myelomas is linked to poor patient survival. We found that Reelin expression was low in primary breast cancer tissue. However, its expression was significantly higher in Her2+ breast cancers metastasizing to the brain. In particular, Reelin was highly expressed in the tumor periphery adjacent to surrounding astrocytes. This augmented Reelin expression was seen in Her2+ metastases, but not in triple negative (TN) primary tumors or in TN breast to brain metastasis cells co-cultured with astrocytes. Furthermore, the elevated expression was sustained in Her2+ cells grown in the presence of the DNA methyltransferase inhibitor 5-azacytidine, indicating epigenetic regulation of Reelin expression. The relative growth and rate of spheroids formation derived from Her2+ primary and BBM cells co-cultured with astrocytes were higher than those of TN primary and BBM cells, and knockdown of both Reelin and Her2 suppressed the astrocyte-induced growth and spheroid forming ability of Her2+ cells. Collectively, our results indicate that within the neural niche, astrocytes epigenetically regulate Reelin expression and its interaction with Her2 leading to increased proliferation and survival fitness.
“Astrocyte-induced Reelin expression drives proliferation of Her2+ breast cancer metastases” by Rahul Jandial, Cecilia Choy, Danielle M Levy, Mike Y Chen, and Khairul I Ansari in Clinical & Experimental Metastasis Journal. Published online February 17 2017 doi:10.1007/s10585-017-9839-9