A collaboration between Dr. Xiaosong Wang and Dr. Rachel Schiff, both from the Lester and Sue Smith Breast Cancer Center at Baylor College of Medicine, discovered a genetic reason for more aggressive forms of luminal B breast cancer subtypes, which are estrogen-receptor positive (ER+).
As detailed in their report published in Nature Communications, entitled, “Recurrent ESR1–CCDC170 rearrangements in an aggressive subset of estrogen receptor-positive breast cancers,” the gene fusion known as ESR1-CCDC170 is common in luminal, ER+ tumors. “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,” said Dr. Wang in a news release from BCM. “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.”
To do so, the collaborators, along with lead authors Dr. Jamunarani Veeraraghavan, Dr. Ying Tan, and Dr. Xi-Xi Cao, studied 200 tumor samples from the Lester and Sue Smith Breast Center’s Tumor Bank and used data from the National Human Genome Research Initiative’s Cancer Genome Atlas. Eight of the 200 tumors were positive for ESR1-CCDC170, a fusion between the estrogen receptor gene and its neighbor. “In a majority of cases this fusion seems to be generated by a tandem duplication of the genetic material spanning the ESR1 and CCDC170 genes,” explained Dr. Wang.
The gene rearrangement caused information transfer to be disrupted within the tumor cells. In order to identify a role for ESR1-CCDC170 in stimulating aggressive cancers, the team introduced the gene fusion into ER+ breast cancer cells. As a result, the cells became more mobile and invasive, allowing them to enhance tumor formation. “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,” stated Dr. Wang.
Adding to the novelty of the team’s work were mechanistic studies. The researchers identified that amino-terminally truncated CCDC170 proteins formed as a result of the gene fusion interact with Gab1 signalosome to enhance the growth factor signaling pathways between cell motility. “The rearrangements between the genes were very cryptic, which makes it very difficult to be detected by conventional cytogenetic approaches,” said Dr. Wang. Added Dr. Schiff, “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.”
Rounding out the team from Baylor were Jin-Ah Kim, Xian Wang, Gary C. Chamness, Dean P. Edwards, Alejandro Contreras, Susan G. Hilsenbeck, and Eric C. Chang. They were accompanied by Sourindra N. Maiti and Laurence J. N. Cooper from the University of Texas MD Anderson Cancer Center.
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