E-cadherin loss induces targetable autocrine activation of growth factor signalling in lobular breast cancer

Teo, K.L.; Gómez-Cuadrado, Laura; Tenhagen, Milou; Byron, Adam; Rätze, Max A K; Amersfoort, Miranda van; Renes, Jojanneke; Strengman, Eric; Mandoli, Amit; Singh, Abhishek A.; Martens, Joost H.A.; Stunnenberg, Hendrik G.; Diest, Paul J. van; Brunton, Valerie G.; Derksen, Patrick W.B.

doi:10.1038/s41598-018-33525-5

Cited by 61 publications

(81 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This is consistent with other reports demonstrating that E-cadherin-mediated adhesion negatively regulates IGF1R activation [37,38]. Furthermore, in breast cancer models, loss of E-cadherin and the subsequent activation of IGF1R signaling results in increased sensitivity to dual IGF1R/Insulin receptor inhibitors, and Akt inhibitors that target downstream receptor pathway activation, even in the presence of activating PIK3CA mutations [36,37]. Interestingly, increased expression of IGF1 is seen in ILC compared to IDC [27,36,39], consistent with reported pathway activation [36,37].…”

Section: Discussionsupporting

confidence: 92%

“…Previously we have shown that loss of E-cadherin promotes hypersensitization of PI3K/Akt pathway activation in response to IGF1, independent of PAPP-A [36], as well as oncogenic mutations in the PI3K/Akt pathway that are prevalent in ILC [5]. This is consistent with other reports demonstrating that E-cadherin-mediated adhesion negatively regulates IGF1R activation [37,38].…”

Section: Discussionsupporting

confidence: 92%

See 1 more Smart Citation

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

Gómez-Cuadrado

Zhao

Souleimanova

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 92%

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

Gómez-Cuadrado

Zhao

Souleimanova

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…ILC is the 6 th most common cancer in women, with an estimated 40,000 new cases in 2019, despite accounting for a smaller proportion of breast cancer cases (~15%) compared to IDC (~75%) 1 . ILC shows distinct signaling in pathways essential for breast cancer growth and proliferation compared to IDCsuch as the WNT4 signaling in response to estrogen stimulus or blockade 2,3 , increased PI3K/Akt signaling 4,5 , enhanced IGF1-IGF1R activation 6 , and dependency on ROS1 7 , which suggest that ILC could benefit from unique treatment strategies. The most distinguishing molecular feature of ILC is loss of E-cadherin, largely arising from inactivating CDH1 mutations.…”

Section: Introductionmentioning

confidence: 99%

Single cell transcriptomic heterogeneity in invasive ductal and lobular breast cancer cells

Chen

Ding

Priedigkeit

et al. 2020

Preprint

View full text Add to dashboard Cite

Invasive lobular breast carcinoma (ILC), one of the major breast cancer histological subtypes, exhibits unique clinical and molecular features compared to the other well-studied ductal cancer subtype (IDC). The pathognomonic feature of ILC is loss of E-cadherin, mainly caused by inactivating mutations within the CDH1 gene, but the extent of contribution of this genetic alteration to ILC-specific molecular characteristics remains largely understudied. To profile these features transcriptionally, we conducted single cell RNA sequencing on a panel of IDC and ILC cell lines, as well as an IDC cell line (T47D) with CRISPR-Cas9-mediated knock out (KO) of CDH1. Inspection of intra-cell line heterogeneity illustrated genetically and transcriptionally distinct subpopulations in multiple cell lines and highlighted rare populations of MCF7 cells highly expressing an apoptosis-related signature, positively correlated with a pre-adaptation signature to estrogen deprivation. Investigation of CDH1 KO-induced alterations showed transcriptomic membranous systems remodeling, elevated resemblance to ILCs in regulon activation, and suggests IRF1 as a potential mediator of reduced proliferation and increased cytokine-mediated immune-reactivity in ILCs.

show abstract

“…As described above, WNT4 in ILC may represent an alternative pathway for the activation of mTOR signaling, potentially in concert with estrogen regulation of WNT4 and low PTEN, as high WNT4-expressing ILC also had decreased phospho-Akt (Supplemental Figure 7E). A recent study by Teo et al linked Akt activation to loss of Ecadherin (the hallmark feature of ILC [4]), but these studies identified this link using ER-negative ILC models (murine p53/CDH1-null lines and IPH-926) [50]. These observations suggest that even within ILC, subsets with distinct modes of PI3K/Akt/mTOR signaling exist.…”

Section: Discussionmentioning

confidence: 99%

Estrogen controls mTOR signaling and mitochondrial function via WNT4 in lobular carcinoma cells

Shackleford

Bordeaux

et al. 2019

Preprint

View full text Add to dashboard Cite

Twitter: @mjsikoraAuthors' contributions MJS, DMR, and SO conceived of the project and experiments. MJS, DMR, EKB, and HMH designed and performed experiments. MJS and DMR developed models for the project. All authors contributed to data analysis and interpretation. MJS wrote the draft manuscript; all authors read and revised the manuscript and have read and approved of this version of the manuscript. AbstractInvasive lobular carcinoma of the breast (ILC) is strongly estrogen-driven, and represents a unique context for estrogen receptor (ER) signaling. In ILC, ER controls the expression of the Wnt ligand WNT4, which is critical for endocrine response and anti-estrogen resistance, yet signaling mediated by WNT4 is poorly understood. We utilized reverse phase protein array (RPPA) to characterize ER and WNT4-driven signaling in ILC cells, and identified WNT4 as a mediator of downstream mTOR signaling via p70-S6K. Independent of mTOR/p70-S6K, ER and WNT4 control levels of MCL-1, which is associated with mitochondrial function. In this context, knockdown of WNT4 caused accumulation of reactive oxygen species and decreased ATP production that precede cell death. WNT4 regulation of both mTOR signaling and MCL-1 levels was also observed in anti-estrogen resistant models of ILC.Further, we identified that high WNT4 expression is associated with similar mTOR pathway activation in serous ovarian cancer tumors, suggesting that this WNT4 pathway is important in multiple tumor types.The identified downstream pathways represent potential targets to inhibit WNT4 signaling in ovarian cancer and overcome anti-estrogen resistance for patients with ILC.

show abstract

E-cadherin loss induces targetable autocrine activation of growth factor signalling in lobular breast cancer

Cited by 61 publications

References 54 publications

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

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

Single cell transcriptomic heterogeneity in invasive ductal and lobular breast cancer cells

Estrogen controls mTOR signaling and mitochondrial function via WNT4 in lobular carcinoma cells

Contact Info

Product

Resources

About