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Inherited Gene Expression Patterns Contribute to Breast Cancer Metastasis Signature, NCI Study Finds

NEW YORK (GenomeWeb News) – Gene signatures linked to breast cancer metastasis appear to reflect both inherited genetic information and somatic mutations, according to new research.
In a paper appearing in yesterday’s issue of Cancer Research, a team of researchers from the National Cancer Institute used microarrays to gauge gene expression in mice with high and low metastatic potential. Subsequent mouse experiments — and data from five sets of human breast cancer tumors — suggest gene expression signatures heralding breast cancer metastasis reflect a combination of inherited and somatic mutations.
“Hopefully in the future we will be able to determine which women are more likely to have a tumor that would metastasize, and we could then tailor therapy specifically for them, avoiding the use of harsh treatments for those with a low probability of metastasis,” senior author Kent Hunter, a senior investigator at NCI’s Center for Cancer Research, said in a statement.
Understanding the progression of metastasis, the movement of cancer cells from the primary tumor site to secondary sites of malignancy, is important for developing treatments for many lethal cancers, the authors explained. Many scientists have traditionally viewed this metastatic progression as the result of somatic mutations arising during an individual’s lifetime.
In contrast, Hunter’s team has found evidence in mouse models and human breast cancers that suggest individuals can also inherit susceptibility to cancer metastasis. For the latest paper, the researchers took that work a step further, looking at whether prognostic gene expression signatures are inherited in the germline or arise somatically.
To do this, they used an Affymetrix GeneChip to compare the gene expression profiles of mouse strains with either a high or low metastatic profile. In doing so, the researchers identified a genetic signature that distinguishes between mice with a high and low susceptibility to cancer metastasis. When they converted this mouse mammary tumor gene signature to a human signature, the researchers found that it could accurately predict human breast cancer outcomes in five different data sets.
To investigate how the stroma, tissue near the tumor, influences metastasis, the researchers transplanted highly metastatic tumor cells into mammary fat pads of mice with high or low metastatic potential. After nearly a month, the researchers failed to find significant differences in metastasis to the lung, suggesting genes in the epithelium, more distant tissues surrounding the tumor, are as or more influential than those in the stroma. The team noted that the highly malignant properties of the tumor cell line may have also contributed to this outcome.
When the researchers measured the gene expression of tumors transplanted into high and low metastatic risk mice, they identified a genetic signature that could predict breast cancer outcomes in four of the five human breast cancer sets. Because the signature encompasses inherited genetic information within the host tissue, the researchers argued that both the stromal and epithelial tissue play a part in prognostic gene expression profiles.
The researchers also did gene expression analyses of five normal, non-neoplastic mouse tissues — whole blood, spleen, thymus, bone marrow, and lung tissue — from high or low metastatic risk mice. Consistent with their notion that inherited genes contribute to metastasis risk, they found that gene expression differences in the spleen and thymus of high and low metastatic risk mice could predict breast cancer outcomes in four of five human data sets. Signatures derived from apparently normal mouse lung tissue, meanwhile, accurately predicted outcomes in all five human data sets tested.
“These results show that both the tumor epithelium and invading stromal tissues contribute to the development of prognostic gene signatures,” Hunter and his co-workers wrote. “Furthermore, analysis of normal tissues and tumor transplants suggests that prognostic signatures result from both somatic and inherited components, with the inherited components being more consistently predictive.”
Next, Hunter noted, the team plans to try to get a better handle on how the epithelium and stroma contribute to tumor progression — work that they hope will yield new strategies for developing cancer therapeutics.

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