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Study Highlights Molecular Changes in Tumor-Neighboring Tissue in Breast Cancer Patients

NEW YORK (GenomeWeb) – New research suggests histologically normal mammary duct cells neighboring cancerous breast tissue can contain genomic changes falling along a gradient with distance from the tumor.

Researchers from the University Health Network, the University of Toronto, and the Ontario Institute for Cancer Research used array-based expression profiling, array comparative genomic hybridization, and other approaches to characterize breast epithelial tissue adjacent to — and distant from — tumors in eight individuals with breast cancer. The results, appearing online today in Nature Communications, pointed to distinct expression modules emanating out from the tumor.

"The fact that changes are already present in different regions of the breast could be important in the delivery of radiation therapy or surgical margin assessment," co-corresponding author Susan Done, a pathology researcher affiliated with the Princess Margaret Cancer Centre, the University of Toronto, and other centers, said in a statement. "We're a long way from bringing this into clinic, but it is something we will think about as we continue our research."

For their analyses, Done and her colleagues assessed breast epithelial cell samples obtained by ductoscopy from eight individuals with primary breast carcinoma during mastectomy surgery, comparing tissue from ducts leading to each individual's tumor with those collected from ducts at nipple sites further from the tumor. They also looked at how potential alterations in the ducts differed depending on distance from the tumor itself.

"Almost all genomic studies of breast cancer have focused on well-established tumors because it is technically challenging to study the earliest mutational events occurring in human breast epithelial cells," University Health Network and University of Toronto researcher Moustafa Abdalla, the study's first author, said in a statement. "Normal breast epithelium from the duct giving rise to a breast cancer has not been previously studied in this way."

With the help of an Agilent kit, for example, the team used single-cell aCGH to track copy number patterns in the samples. Meanwhile, expression profiles in the samples were assessed using Agilent expression arrays. Together with invasion assays, immunofluorescence-based imaging, and other analyses, the molecular data highlighted a "cancerization" field marked by clusters of cells with shared expression features found at different distances from the tumor.

The team also saw copy number alterations in the mammary duct tissue surrounding breast tumors, supporting the notion that tissue around tumors is "remarkably unstable with heterogeneous and varied genetic alterations." Even so, the copy number changes did not necessarily coincide with gene transcript abundance and appeared less closely tied to tumor proximity than the expression modules.

At least some of the altered signaling pathways in the cancer-free epithelial cells seemed to coincide with features such as tumor grade, the researchers noted. By continuing to delve into the alterations identified in in ductal tissue surrounding tumors, they suspect that it will also be possible to get new insights into the early stages of cancer development.

"[O]ur analyses indicate that tumor initiation may not be driven by [copy number alterations] and that expression data points to an altered field surrounding the tumors," the authors wrote. "Identifying such transcriptomic alterations, preceding tumorigenesis, would allow us to better understand carcinoma development as well as develop new screening and treatment approaches."