Identification of stromal genes differentially expressed in lobular breast cancer highlights role for pregnancy-associated-plasma protein-A

Abstract

Background: Invasive lobular carcinoma (ILC) is the second most common histological subtype of breast cancer and exhibits a number of clinico-pathological characteristics that are distinct from the more common invasive ductal carcinoma (IDC). Despite these differences, ILC is treated in the same way as IDC. We set out to identify alterations in the tumor microenvironment (TME) of ILC with potential clinical significance. Methods:We used laser-capture microdissection (LCM) to separate tumor epithelium from stroma in 23 ER+ ILC samples. Gene expression analysis was used to identify genes that are enriched in the stroma of ILC, but not IDC or normal breast.Results: 45 genes involved in regulation of the extracellular matrix (ECM) were enriched in the stroma of ILC, but not stroma from ER+ IDC or normal breast. Of these, 10 were expressed in cancer-associated fibroblasts (CAFs) and were increased in ILC compared to IDC in bulk gene expression datasets. PAPPA was the most enriched in the stroma compared to the tumor epithelial compartment in ILC. PAPPA encodes pregnancy-associated plasma protein-A (PAPP-A), a metalloproteinase that cleaves insulin-like binding protein-4 (IGFBP-4) increasing IGF-1 bioavailability and subsequent downstream signaling. Analysis of PAPPA and IGF1 associated genes identified a paracrine signaling pathway and active PAPP-A was shown to be secreted from primary CAFs. Comprehensive survival analysis across 3000 breast cancers identified PAPPA as a potential ILC-specific prognostic marker.Conclusions: This is the first study to demonstrate molecular differences in the TME between ILC and IDC and identifies PAPP-A, a CAF-derived proteinase, as a potential prognostic marker.

Atlas of Lobular Breast Cancer Models: Challenges and Strategic Directions

“…The realization that cell-cell and cell-matrix interactions within the complex tumor environment regulate primary tumor growth, metastatic spread, and response to therapy provides potential new ILC therapeutic opportunities [160,[212][213][214]. Similarly, as we now understand more about the unique ILC tumor microenvironment, it will be necessary to model the different immune cell populations, cancer-associated fibroblasts, and matrix components [29,160,213,215]. Moreover, the establishment of PDX models from unique ILC metastatic sites such as leptomeninges and ovaries would provide additional information on how the tumor-related metastatic niche controls the outgrowth of disseminated ILC cells.…”

Invasive Lobular Carcinoma of the Breast: Ongoing Trials, Challenges, and Future Directions

“…Studies of tumor stroma identify differences between ILC and IDC, including an increase in the presence of cancer associated fibroblasts in ILC. This may result in increased levels of the metalloproteinase pregnancyassociated plasma protein-A (PAPP-A), leading to increased insulin-like growth factor (IGF)-1 and activation of its signaling pathway, another putative treatment target in ILC [59,60].…”