A team of researchers led by Goutham Narla, MD, PhD, at Case Western Reserve University School of Medicine and University Hospitals Case Medical Center, and collaborators at the Mount Sinai School of Medicine and Erasmus Medical Center, have discovered a gene variant that drives the spread of breast cancer.

The results of the study are published in Science Translational Medicine, and lays the early foundation for predicting which breast cancer patients may develop more aggressive disease and for designing more effective treatments.

Genetically complex
“Breast cancer is a genetically complex disease and it remains a challenge to predict disease outcomes and which patients may benefit from more aggressive treatment,” says Narla, assistant professor at Case Western Reserve University School of Medicine and medical geneticist at UH Case Medical Center Seidman Cancer Center. “Our research has uncovered a promising gene marker that will not only help us better identify tumors that behave badly but provide a basis for developing and ‘personalizing‘ therapies to better treat our patients.”

Recurrence and metastasis
The research team discovered that a mutant gene, KLF6-SV1, was linked to the recurrence and metastasis in women with breast cancer. The incorrect splicing of the KLF6 gene essentially creates a protein that causes cancer cells to spread or metastasize. The researchers examined the tumors of 671 breast cancer patients in a tumor bank atErasmus University Medical Center (Rotterdam, The Netherlands) and found that those whose tumors expressed high levels of the gene variant were 50 percent more likely to die. Since recurrence and metastasis are the major causes of death in breast cancer, this finding will provide a new direction of research to both identify women at risk and to develop targeted drugs that block the process of metastasis.

“This study presents biological proof that this splice variant can potentially be a marker for determining which early stage breast cancer patients will have disease progression,” adds Narla. “More studies need to be done, but this could provide an important prognostic marker to determine which patients need to be treated more aggressively or watched more closely.”

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Harrington Distinguished Scholar
Narla came to UH Case Medical Center and Case Western Reserve in spring, 2012, from Mt. Sinai and is the first Harrington Distinguished Scholar (Early Career Award). The inaugural award provides physician-scientists with the ability to tap into grant funding and a peer network of innovators and mentors within the infrastructure of the Harrington Discovery Institute at UH Case Medical Center.

Through the Harrington Distinguished Scholars Program, physician-scientists are chosen to practice medicine at University Hospitals Case Medical Center and to hold a faculty positions at Case Western Reserve University School of Medicine. Over the next decade, University Hospitals Harrington Discovery Institute, the nonprofit arm of The Harrington Project for Discovery & Development, a new and powerful national model that addresses a set of major challenges in advancing medicine,plans to recruit 10-20 physician-scientists of outstanding promise anda determined interest in advancing the treatment of patients.

Tumor suppressor genes
Narla’s laboratory focuses on the identification and characterization of the genes and pathways involved in cancer metastasis. By studying the functional role of the KLF6 tumor suppressor gene, Narla and his team have identified new signaling pathways regulated by this gene family thus providing new insight into cancer diagnosis and treatment. The team’s research found that KLF6 and FOXO1, both tumor suppressor genes, are turned off as cancer spreads through the body. Since first discovering the KLF6 gene 13 years ago as a medical student at Mount Sinai School of Medicine in the laboratory of Scott Friedman, Narla has been involved in the identification and characterization of the gene and its role in cancer development.

Basic mechanisms regulating cancer
“In this new research as well as previous studies, Goutham and his team have uncovered important and previously unrecognized genetic markers in cancer,” said Stanton Gerson, MD, Director of the Case Comprehensive Cancer Center and the UH Case Medical Center Seidman Cancer Center. “This work highlights how understanding the basic mechanisms regulating cancer development and progression can lead to significant advances in the treatment of cancer. We are so pleased to have a physician-scientist of his caliber at our cancer center and are excited about the impact of this important work.”

Narla will work with the breast cancer team, led by Lyndsay Harris, MD, to study further KLF6-SV1’s potential as a prognostic marker for patients with poor outcomes. The group also will work to develop novel therapeutics that can turn the protein off and cause the cells to become less aggressive.

The role of KLF6-SV1
In their researchm the scientists noted that KLF6-SV1 overexpression in mammary epithelial cell lines resulted in an epithelial-to-mesenchymal?like transition and drove aggressive multiorgan metastatic disease in multiple in vivo models. Furthermore,KLF6-SV1 loss-of-function studies demonstrated reversion to an epithelial and less invasive phenotype. Combinging thesefindings implicates KLF6-SV1 as a key driver of breast cancer metastasisdistinguishing between indolent and lethal early-stage disease and provides a potential therapeutic target for invasive breast cancer.

“We look forward to continuing this work to further define the role of KLF6-SV1 on the molecular basis of tumor progression and metastasis in breast cancer,” says Harris, Director of the Breast Cancer Program at UH Case Medical Center and Professor, Medicine-Hematology/Oncology at the School of Medicine. “These findings provide us with a biomarker of more aggressive disease and a target for new therapies. This will potentially enable us to develop more personalized treatments for patients and thereby reduce breast cancer mortality.”

Hatami R, Sieuwerts AM, Izadmehr S, Yao Z, Qiao RF, Papa L, Look MP, Smid M, et al. KLF6-SV1 Drives Breast Cancer Metastasis and Is Associated with Poor Survival. Sci Transl Med 23 January 2013 5:169ra12. DOI:10.1126/scitranslmed.3004688
Olson OC and Joyce JA. A Splicing Twist on MetastasisSci Transl Med 23 January 2013: Vol. 5, Issue 169, p. 169fs2 Sci. Transl. Med. DOI: 10.1126/scitranslmed.3005424.

Photo 1: Goutham Narla, MD, PhD, at Case Western Reserve University School of Medicine and University Hospitals Case Medical Center. Photo courtesy: Case Comprehensive Cancer Center | 11100 Euclid Avenue | Cleveland, Ohio 44106-5065

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