Researchers from the Lester and Sue Smith Breast Center at Baylor College of Medicine and the University of Texas MD Anderson Cancer Center have identified genetic alterations thought to contribute to the development of more aggressive forms of breast cancer.
The study, entitled “Recurrent ESR1–CCDC170 rearrangements in an aggressive subset of estrogen receptor-positive breast cancers,” was published in the acclaimed journal Nature Communications and led by Dr. Xiaosong Wang, an assistant professor of medicine — hematology and oncology and of molecular and cellular biology at BCM.
Partly relying on data available through the National Human Genome Research Initiative’s Cancer Genome Atlas project, the researchers employed large-scale analysis of breast cancer transcriptomes and copy number alterations in aggressive and endocrine-resistant luminal B tumors, an aggressive molecular subtype of estrogen-receptor positive (ER+) breast cancer, thus identifying recurrent rearrangements between the estrogen receptor gene ESR1 and its neighbor CCDC170.
Dr. Wang explained in a BCM press release, “While expressing the estrogen receptor, the luminal B breast cancers usually have higher tumor grade, larger tumor size, and poor prognosis, with most cases difficult to treat by endocrine therapy. We wanted to gain a deeper understanding about the genetic alterations underlying this particular form of breast cancer, because we do not know about what malfunctions potentially cause this form to be more aggressive.”
Screening of 200 ER+ breast cancers samples available through the Lester and Sue Smith Breast Center’s Tumor Bank, the researchers identified 8 ESR1–CCDC170-positive tumors. This genetic fusion encoded amino-terminally truncated CCDC170 proteins (ΔCCDC170) that upon in vitro transfection into ER+ breast cancer cells, led to increased cell motility, growth, reduced endocrine sensitivity and enhanced tumor formation, likely accounting for the observed aggressiveness of ESR1-CCDC170-positive human tumors.
“The rearrangements between the genes were very cryptic, which makes it very difficult to be detected by conventional cytogenetic approaches,” added Dr. Wang. “This finding is important because it sheds new light on a much needed better understanding about what may cause these tumors to be more aggressive.”
Dr. Rachel Schiff, associate professor in the Smith Breast Center at Baylor and co-adviser for this study also highlighted in the press release, “The aggressive luminal B subtype of breast cancer is a heterogeneous and complex disease. In the era of precision medicine, the current study emphasizes the importance and promise of integrative genomic research methodologies. This approach can identify genetic aberrations that may drive the development and progression of these aggressive tumors and that may guide more personalized effective therapeutic strategies.”
In addition to Dr. Wang, the study included co-lead authors Jamunarani Veeraraghavan, Ying Tan, and Xi-Xi Cao; Jin-Ah Kim; Xian Wang; Gary C. Chamness; Dean P. Edwards; Alejandro Contreras; Susan G. Hilsenbeck; Eric C. Chang, all of Baylor, and Sourindra N. Maiti and Laurence J. N. Cooper of the University of Texas M.D. Anderson Cancer Center.
The research was funded by grants through the Department of Defense’s Congressionally Directed Medical Research Programs and the Nancy Owens Memorial Foundation: Susan G. Komen for the Cure and the National Institutes of Health.