Stroma Expression Patterns in Breast Cancer

Institution: Stanford University
Investigator(s): Robert West, M.D., Ph.D. - Robert West, M.D., Ph.D. -
Award Cycle: 2009 (Cycle 15) Grant #: 15NB-0156A Award: $188,097
Award Type: IDEA Competitive Renewal
Research Priorities
Biology of the Breast Cell>Pathogenesis: understanding the disease

This is a collaboration with: 15NB-0156 -

Final Report (2012)

Our first goal has been to generate a clinically useful test to assess the presence of stromal response signatures in breast cancer samples. We have developed three assays towards this goal. We have identified gene expression profiles for two distinct stromal signatures in breast carcinoma of fibroblast (aka DTF) and macrophage (aka CSF1) response and found them to be correlated with clinicopathological features, including outcome.

First, we developed a core gene signature of the DTF fibroblast and CSF1 macrophage stromal responses in gene microarrays, independent of specific platforms. Second, we developed a five marker immunohistochemical panel for both the DTF fibroblast and CSF1 macrophage stromal responses. These two panels of gene markers accurately assess the presence of the stromal signatures and could be easily adopted in the clinical laboratory. Third, we have developed a robust RNA sequencing method for quantification of RNA in archival material and have used this signature to identify the DTF fibroblast and CSF1 macrophage signatures and three additional stromal signatures.

The core signatures for the DTF fibroblast and CSF1 macrophage stromal responses (which contain 66 and 112 genes respectively) include genes chosen because they showed highly coordinate expression across multiple independent breast cancer datasets and were the most highly representative genes of the DTF fibroblast and CSF1 macrophage signatures, as previously described.

We now have identified three additional stromal signatures. The first involves cases that have no or very little expression of the DTF core genes. This "DTF negative" signature is not simply the cases that are not classified as "DTF positive". In fact, the majority of cases do not fall into either category. These "DTF negative" cases have their own characteristic gene signature and clinicopathologic features. The other two have been developed from the study of fibroblastic processes using the same approach that identified the original DTF fibroblast signature. These two additional signatures, derived from Elastofibroma and Fibroma of Tendon Sheath processes, are largely independent of the other signatures and identify groups of breast cancers with distinct clincopathologic features. We have also found that these stromal signatures are present at breast neoplasia stages prior to the development of invasive breast cancer.

We have found that the DTF signature can be identified at very early stages of breast neoplasia, including columnar cell change. The variations of these stromal reaction patterns from the primary to the metastasis shed light on the relationship between the neoplastic cells and the non-neoplastic cells in the TME. The preservation of the CSF1 macrophage response pattern in metastases lends support to targeting the CSF1 pathway in cancer.



Endogenous versus tumor-specific host response to breast carcinoma: a study of stromal response in synchronous breast primaries and biopsy site changes.
Periodical:Clinical Cancer Research
Index Medicus: Clin Cancer Res
Authors: Wu J, Beck A, Pate L, Witten D, Zhu S, Montgomery K, Allison K, van de Rijn M, West RB
Yr: 2011 Vol: 17 Nbr: 3 Abs: Pg:437-46

Variations in stromal signatures in breast and colorectal cancer metastases.
Periodical:Journal of Pathology
Index Medicus: J Pathol
Authors: Webster JA, Beck AH, Sharma M, Espinosa I, and West R
Yr: 2010 Vol: 222 Nbr: 2 Abs: Pg:158-165