TY - JOUR
T1 - Characterisation of the Stromal Microenvironment in Lobular Breast Cancer
AU - Gomez Cuadrado, Laura
AU - Bullock, Esme
AU - Mabruk, Zeanap
AU - Zhao, Hong
AU - Souleimanova , Margarita
AU - Rimmer Noer, Pernille
AU - Turnbull, Arran K
AU - Oxvig, Claus
AU - Bertos, Nicholas
AU - Byron, Adam
AU - Dixon, MIchael
AU - Park, Morag
AU - Haider, Syed
AU - Natrajan, Rachael
AU - Sims, Andrew H
AU - Brunton, Valerie G
N1 - Funding Information:
ILC samples for LCM were obtained from the McGill University Health Centre: Breast Cancer Functional Genomics Initiative Biobank, Montreal, Canada (study identifiers SUR-99-780 and SUR-2000-966). Samples for generation of CAFs were obtained from the NHS Lothian Tissue Governance Committee, Edinburgh, United Kingdom (approval number 15/ES/0094).
Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2022/2/11
Y1 - 2022/2/11
N2 - Invasive lobular carcinoma (ILC) is the second most common histological subtype of breast cancer, and it exhibits a number of clinico-pathological characteristics distinct from the more common invasive ductal carcinoma (IDC). We set out to identify alterations in the tumor microenvironment (TME) of ILC. We used laser-capture microdissection to separate tumor epithelium from stroma in 23 ER+ ILC primary tumors. Gene expression analysis identified 45 genes involved in regulation of the extracellular matrix (ECM) that were enriched in the non-immune stroma of ILC, but not in non-immune 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, with PAPPA and TIMP2 being associated with better survival in ILC but not IDC. PAPPA, a gene involved in IGF-1 signaling, was the most enriched in the stroma compared to the tumor epithelial compartment in ILC. Analysis of PAPPA- and IGF1-associated genes identified a paracrine signaling pathway, and active PAPP-A was shown to be secreted from primary CAFs. This is the first study to demonstrate molecular differences in the TME between ILC and IDC identifying differences in matrix organization and growth factor signaling pathways
AB - Invasive lobular carcinoma (ILC) is the second most common histological subtype of breast cancer, and it exhibits a number of clinico-pathological characteristics distinct from the more common invasive ductal carcinoma (IDC). We set out to identify alterations in the tumor microenvironment (TME) of ILC. We used laser-capture microdissection to separate tumor epithelium from stroma in 23 ER+ ILC primary tumors. Gene expression analysis identified 45 genes involved in regulation of the extracellular matrix (ECM) that were enriched in the non-immune stroma of ILC, but not in non-immune 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, with PAPPA and TIMP2 being associated with better survival in ILC but not IDC. PAPPA, a gene involved in IGF-1 signaling, was the most enriched in the stroma compared to the tumor epithelial compartment in ILC. Analysis of PAPPA- and IGF1-associated genes identified a paracrine signaling pathway, and active PAPP-A was shown to be secreted from primary CAFs. This is the first study to demonstrate molecular differences in the TME between ILC and IDC identifying differences in matrix organization and growth factor signaling pathways
KW - lobular breast cancer
KW - tumor microenvironment;
KW - cancer-associated fibroblasts
U2 - 10.3390/cancers14040904
DO - 10.3390/cancers14040904
M3 - Article
SN - 2072-6694
JO - Cancers
JF - Cancers
ER -