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Transcriptome Analysis of At-Risk Breast Cells Uncovers Expression Shifts

NEW YORK — Researchers have characterized the transcriptome of cells at increased risk of developing into breast tumors.

Cells located near breast tumors, despite appearing normal, are at increased risk of developing into a secondary breast cancer. Using the conditionally reprogrammed cell technique, researchers from Georgetown University grew normal breast epithelial cells isolated from the same breast in which patients had a tumor. As they presented in Science Reports on Friday, the researchers also uncovered altered transcriptomes within these malignancy-adjacent cells, including changes that shifted them to be more like mammary stem cells.

By better understanding these at-risk cells, the researchers said further insight could be gleaned into how recurrences arise.

"We hope that our findings will help lead to more precise and directed screening in the future, sparing women unneeded procedures as we currently screen almost all women between the ages of 40 to 70, sometimes very aggressively," senior author Priscilla Furth, professor of oncology and medicine at Georgetown Lombardi, said in a statement.

She and her colleagues collected high-risk noncancerous samples from 25 women with different types of breast cancer who underwent mastectomies. From these samples, the researchers generated conditionally reprogrammed cell cultures, which enabled them to grow and study normal breast epithelial cells. Normal epithelial cells, they noted, can otherwise be difficult to study as they are slow growing cells and their cultures often become contaminated with other cell types, especially fibroblasts.

Overall, they found that viability and formation of mammospheres varied across samples but were stable across the three mammary-specific media they used.

The researchers meanwhile conducted RNA-sequencing analysis of the initial high-risk noncancerous samples as well as of matched invasive tumor samples from eight individuals. They noted links between some samples' behavior in culture and their gene expression. For instance, many of the high-viability cells also had higher expression of many target genes of E2F transcription factors, which are linked to cell proliferation.

The researchers further focused their analysis on samples from women who underwent chemotherapy prior to surgery. Treatment, they found, altered the transcriptomes of the high-risk noncancerous cells to resemble more closely those of mammary stem cells. Genes including LIFR and THY1 were upregulated, while genes like CD24 were downregulated.

This shift to stem-cell like state could be an indicator of either a post-treatment healing response or of future cancer stem cell development, the researchers noted.

Furth and colleagues additionally found that some high-risk noncancerous samples and tumor samples expressed genes typically linked to pregnancy. Some samples, for instance, had increased expression of BIRC5 and STAT5A, which have previously also been tied to breast cancer. They further noted that the expression patterns of the pregnancy-related genes differed in their samples versus patterns observed during the luteal phase of menstruation. Future studies, they added, should consider menstrual cycle phase at time of sample collection.

These different behavioral and transcriptomic profiles could indicate different risk profiles for these cells and patients, the researchers added. The findings, they noted, could "provide a baseline for further development of possible prognostic platforms for breast cancer risk," though they noted that such "platforms would be challenging to build."

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