Characterisation of the Stromal Microenvironment in Lobular Breast Cancer

Laura Gómez-Cuadrado; Esme Bullock; Zeanap Mabruk; Hong Zhao; Margarita Souleimanova; Pernille Rimmer Noer; Arran K. Turnbull; Claus Oxvig; Nicholas Bertos; Adam Byron; J. Michael Dixon; Morag Park; Syed Haider; Rachael Natrajan; Andrew H. Sims; Valerie G. Brunton

doi:10.3390/cancers14040904

Characterisation of the Stromal Microenvironment in Lobular Breast Cancer

Laura Gómez-Cuadrado, Esme Bullock, Zeanap Mabruk, Hong Zhao, Margarita Souleimanova, Pernille Rimmer Noer, Arran K. Turnbull, Claus Oxvig, Nicholas Bertos, Adam Byron, J. Michael Dixon, Morag Park, Syed Haider, Rachael Natrajan, Andrew H. Sims, Valerie G. Brunton^*

^*Corresponding author for this work

Department of Molecular Biology and Genetics - Cellular Health, Intervention, and Nutrition

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

13 Citations (Scopus)

Abstract

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.

Original language	English
Article number	904
Journal	Cancers
Volume	14
Issue	4
ISSN	2072-6694
DOIs	https://doi.org/10.3390/cancers14040904
Publication status	Published - Feb 2022

Keywords

Cancer-associated fibroblasts
Lobular breast cancer
Tumor microenvironment

Access to Document

10.3390/cancers14040904Licence: CC BY

Cite this

@article{bc38a7ff268e47b7b89e1647ba13fc3f,

title = "Characterisation of the Stromal Microenvironment in Lobular Breast Cancer",

abstract = "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.",

keywords = "Cancer-associated fibroblasts, Lobular breast cancer, Tumor microenvironment",

author = "Laura G{\'o}mez-Cuadrado and Esme Bullock and Zeanap Mabruk and Hong Zhao and Margarita Souleimanova and Noer, {Pernille Rimmer} and Turnbull, {Arran K.} and Claus Oxvig and Nicholas Bertos and Adam Byron and Dixon, {J. Michael} and Morag Park and Syed Haider and Rachael Natrajan and Sims, {Andrew H.} and Brunton, {Valerie G.}",

note = "Publisher Copyright: {\textcopyright} 2022 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2022",

month = feb,

doi = "10.3390/cancers14040904",

language = "English",

volume = "14",

journal = "Cancers",

issn = "2072-6694",

publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",

number = "4",

}

TY - JOUR

T1 - Characterisation of the Stromal Microenvironment in Lobular Breast Cancer

AU - Gómez-Cuadrado, Laura

AU - Bullock, Esme

AU - Mabruk, Zeanap

AU - Zhao, Hong

AU - Souleimanova, Margarita

AU - Noer, Pernille Rimmer

AU - Turnbull, Arran K.

AU - Oxvig, Claus

AU - Bertos, Nicholas

AU - Byron, Adam

AU - Dixon, J. Michael

AU - Park, Morag

AU - Haider, Syed

AU - Natrajan, Rachael

AU - Sims, Andrew H.

AU - Brunton, Valerie G.

PY - 2022/2

Y1 - 2022/2

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 - Cancer-associated fibroblasts

KW - Lobular breast cancer

KW - Tumor microenvironment

UR - http://www.scopus.com/inward/record.url?scp=85124322034&partnerID=8YFLogxK

U2 - 10.3390/cancers14040904

DO - 10.3390/cancers14040904

M3 - Journal article

C2 - 35205651

AN - SCOPUS:85124322034

SN - 2072-6694

VL - 14

JO - Cancers

JF - Cancers

IS - 4

M1 - 904

ER -

Characterisation of the Stromal Microenvironment in Lobular Breast Cancer

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Cite this