Loss of E-cadherin Enhances IGF1–IGF1R Pathway Activation and Sensitizes Breast Cancers to Anti-IGF1R/InsR Inhibitors

Abstract

Insulin-like growth factor 1 (IGF1) signaling regulates breast cancer initiation and progression and associated cancer phenotypes. We previously identified E-cadherin () as a repressor of IGF1 signaling and in this study examined how loss of E-cadherin affects IGF1R signaling and response to anti-IGF1R/insulin receptor (InsR) therapies in breast cancer. Breast cancer cell lines were used to assess how altered E-cadherin levels regulate IGF1R signaling and response to two anti-IGF1R/InsR therapies. proximity ligation assay (PLA) was used to define interaction between IGF1R and E-cadherin. TCGA RNA-seq and RPPA data were used to compare IGF1R/InsR activation in estrogen receptor-positive (ER+) invasive lobular carcinoma (ILC) and invasive ductal carcinoma (IDC) tumors. ER+ ILC cell lines and xenograft tumor explant cultures were used to evaluate efficacy to IGF1R pathway inhibition in combination with endocrine therapy. Diminished functional E-cadherin increased both activation of IGF1R signaling and efficacy to anti-IGF1R/InsR therapies. PLA demonstrated a direct endogenous interaction between IGF1R and E-cadherin at points of cell-cell contact. Increased expression of IGF1 ligand and levels of IGF1R/InsR phosphorylation were observed in E-cadherin-deficient ER+ ILC compared with IDC tumors. IGF1R pathway inhibitors were effective in inhibiting growth in ER+ ILC cell lines and synergized with endocrine therapy and similarly IGF1R/InsR inhibition reduced proliferation in ILC tumor explant culture. We provide evidence that loss of E-cadherin hyperactivates the IGF1R pathway and increases sensitivity to IGF1R/InsR targeted therapy, thus identifying the IGF1R pathway as a potential novel target in E-cadherin-deficient breast cancers. .

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

“…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].…”

“…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]. 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].…”

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

“…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.…”

Glutamate Ionotropic Receptor Kainate Type Subunit 3 (GRIK3) promotes epithelial‐mesenchymal transition in breast cancer cells by regulating SPDEF/CDH1 signaling

“…In addition, it has shown that E‐cadherin improves IGF1R recruitment to adherens junctions, possibly resulting in receptor sequestration and signaling repression. The loss of functional E‐cadherin would impair the adherens junction formation, and release IGF1R to re‐localize to the entirety of the cell membrane where the IGF1 ligand is easily bound for initiating cancer signaling …”

“…It has been shown that GRIK3 is enriched in the neuroactive ligand receptor interaction pathway and haploinsufficiency of GRIK3 may be responsible for the severe developmental delay. 2,9,10 Interestingly, a previous study indicated that, in breast cancer, multiple estradiol (E2) stimulated or inhibited genes also enriched in the neuroactive ligand receptor interaction pathway were able to affect the cell proliferation. 11 On the basis of the current studies, we proposed that GRIK3 might function in the development of breast cancer.…”