February 7, 2012
Understanding How Early Breast Tumors Become Deadly: A Small Group Of Molecules Might Hold The Answer
Some early-stage breast cancers are potentially harmless, but others invade surrounding healthy tissue and become deadly.
This study has identified a small pattern of molecules that highlights important differences between early-stage breast tumors and invasive, deadly ones.
The findings might lead to a way to identify early tumors that will likely become invasive.
Researchers have discovered a restricted pattern of molecules that differentiate early-stage breast tumors from invasive, life-threatening cancer. They also found a similar molecular signature that correlated with the aggressiveness of invasive tumors, and with the time to metastasis and overall survival.
Researchers at the Ohio State University Comprehensive Cancer Center — Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC — James) who led the study say the findings could offer new strategies for treating breast cancer by blocking progression to life-threatening invasive cancer.
The researchers investigated a common type of early-stage breast cancer called ductal carcinoma in situ (DCIS). DCIS tumors are confined to the milk duct, and, though small, they are detectable by mammography. They can sometimes grow and spread beyond the milk duct into surrounding healthy tissue, a stage called invasive ductal carcinoma.
The study compared the pattern of molecules called microRNAs in DCIS to the pattern present in invasive ductal cancer. It identified nine microRNAs that distinguished invasive cancer from DCIS.
“The transition from DCIS to invasive ductal cancer is a key event in breast cancer progression, but it remains poorly understood,” says principal investigator Dr. Carlo M. Croce, director of Ohio State´s Human Cancer Genetics program and a member of the OSUCCC — James Molecular Biology and Cancer Genetics Program.
“These findings suggest that this ℠micro-signature´ might be used to identify DCIS tumors that are at high-risk for becoming invasive cancer.”
MicroRNAs are a class of molecules that help control the types and quantity of proteins cells make. Work by Croce and others has shown that microRNAs are often dysregulated during cancer development, and it has suggested that the molecules offer new biomarkers of disease, and that restoring key microRNAs to normal levels might offer a new approach to cancer treatment.
First author and cancer researcher Dr. Stefano Volinia notes that high expression of one of those molecules, called miR-210, correlates with tumor aggressiveness and with time to metastasis and overall survival.
“If we could inhibit the few miRNAs associated with tumor invasiveness, perhaps we could arrest tumor progression at the harmless, pre-invasive state,” says Volinia, an assistant professor of molecular virology, immunology and medical genetics and of biomedical informatics.
For this study, Croce, Volinia and their colleagues studied microRNA profiles from data collected using whole-genome deep sequencing. They examined 80 cases of invasive ductal carcinoma, eight of DCIS, and six of normal breast biopsies.
Comparing DCIS and invasive cancer samples showed nine microRNAs that formed an “invasiveness micro-signature.” Three of these miRNAs (let-7d, miR-210, and -221) showed the most extreme changes in expression levels. Relative to their levels in normal breast tissue, the three were down-regulated in DCIS, then up-regulated in invasive cancer.
“That told us that progression from in-situ ductal cancer to invasive cancer involves a reversal of miRNA expression,” Croce says.
Funding from the National Cancer Institute and from the Associazione Italiana per la Ricerca sul Cancro, and the Italian Progetti di Ricerca di Interesse Nazionale Ministero dell´Istruzione dell´UniversitÃ e della Ricerca 2008 supported this research.
Other researchers involved in this study were Timothy F. Wise, Jeffrey J. Palatini and Kay F. Huebner with The Ohio State University; and Marco Galasso, and Maria Elena Sana of UniversitÃ degli Studi, Ferrara, Italy.
The Ohio State University Comprehensive Cancer Center — Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (cancer.osu.edu) strives to create a cancer-free world by integrating scientific research with excellence in education and patient-centered care, a strategy that leads to better methods of prevention, detection and treatment. Ohio State is one of only 41 National Cancer Institute (NCI)-designated Comprehensive Cancer Centers and one of only seven centers funded by the NCI to conduct both phase I and phase II clinical trials. The NCI recently rated Ohio State´s cancer program as “exceptional,” the highest rating given by NCI survey teams. As the cancer program´s 210-bed adult patient-care component, The James is a “Top Hospital” as named by the Leapfrog Group and one of the top 20 cancer hospitals in the nation as ranked by U.S. News & World Report.
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