Decoupling of the PI3K Pathway via Mutation Necessitates Combinatorial Treatment in HER2+ Breast Cancer

Korkola, James E.; Collisson, Eric A.; Heiser, Laura M.; Oates, Chris J.; Bayani, Nora; Itani, Solomon; Esch, Amanda; Thompson, Wallace; Griffith, Obi L.; Wang, Nicholas J.; Kuo, Wen‐Lin; Cooper, Brian; Billig, Jessica I.; Ziyad, Safiyyah; Hung, Jenny; Jakkula, Lakshmi R.; Feiler, Heidi S.; Lu, Yiling; Mills, Gordon B.; Spellman, Paul T.; Tomlin, Claire J.; Mukherjee, Sach; Gray, Joe W.

doi:10.1371/journal.pone.0133219

Cited by 19 publications

(27 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A STR profile of 21MT1 is not available from the ATCC. The 21MT1 cells used in this study generated a profile that is highly similar to their counterpart that was studied and reported in prior studies in that there is a 15/16 match (94%) with the only difference being loss of an allele in our 21MT1 cell . The HER‐2 amplification status in 21MT1 and JIMT1 cells used in this study has been independently verified by fluorescence in situ hybridization (not shown).…”

Section: Methodssupporting

confidence: 72%

GRB7 dependent proliferation of basal‐like, HER‐2 positive human breast cancer cell lines is mediated in part by HER‐1 signaling

Luoh

Wagoner

Wang

et al. 2019

Molecular Carcinogenesis

View full text Add to dashboard Cite

GRB7 gene encodes a multi-domain signal transduction molecule and is part of the core of the HER-2 amplicon. GRB7 is commonly co-amplified and overexpressed with HER-2 in human breast cancer. This study addresses the role of GRB7 in HER-2 positive human breast cancers resistant to HER-2 targeted therapy. HCC1954, 21MT1, and JIMT1 are basal like HER-2 positive breast cancer cell lines based on expression profiling. These three cell lines are resistant to trastuzumab and lapatinib treatment. Knockdown of GRB7 protein expression with siRNA transfection as well as lentiviral vector mediated shRNA over-expression decreased the growth of HCC1954, 21MT1, and JIMT1 cells in vitro and the growth of tumor xenografts these cells formed in animal models. When assayed by ki-67 staining and TUNEL assay, the mechanism of reduced tumor xenograft growth appeared to be distinct. Reduced proliferation and increased apoptosis were seen in 21MT1 cells, while reduced proliferation was seen in HCC1954 cells and increased apoptosis in JIMT1 cells. Phospho-proteome profiling found HER-1 tyrosine phosphorylation was reduced with GRB7 knockdown in JIMT1 cells. Immuno-blotting and immuno-precipitation experiments found HER-1 phosphorylation was reduced with GRB7 knock down in all three cell lines. HER-1 knock down via siRNA transient transfection as well as blocking HER-1 function with panitumumab decreased proliferation of all three cell lines in vitro. Our study finds that GRB7 has an essential growth promoting function which is mediated in part by HER-1 activation. The potential of HER-1 targeting in therapy resistant HER-2 positive breast cancer merits further study.

show abstract

Section: Methodssupporting

confidence: 72%

GRB7 dependent proliferation of basal‐like, HER‐2 positive human breast cancer cell lines is mediated in part by HER‐1 signaling

Luoh

Wagoner

Wang

et al. 2019

Molecular Carcinogenesis

View full text Add to dashboard Cite

show abstract

“…For example, ten patients with PIK3CA -wild type (WT) carcinoma each had PIK3CA exon-20 mutated proliferative lesions present in the same breast tissue specimen [11]. Activating PIK3CA mutations have been shown to evoke downstream PI3K network signaling that fuels cellular transformation and cancer growth in vitro , but their in vivo activity within lesional tissue is more difficult to establish[14, 15], in light of intra-network inhibitory feedback loops or inter-network cross-talk[2–4, 16, 17]. …”

Section: Introductionmentioning

confidence: 99%

Multiplexed imaging reveals heterogeneity of PI3K/MAPK network signaling in breast lesions of known PIK3CA genotype

Jacob

Gray

Troxell

et al. 2016

Breast Cancer Res Treat

Self Cite

View full text Add to dashboard Cite

Purpose Activating genetic changes in the phosphatidylinositol-3-kinase (PI3K) signaling pathway are found in over half of invasive breast cancers (IBC). Previously, we discovered numerous hotspot PIK3CA mutations in proliferative breast lesions. Here, we investigate the spatial nature of PI3K pathway signaling and its relationship with PI3K genotype in breast lesions. Methods We identified PI3K phosphosignaling network signatures in columnar cell change (CCL), usual ductal hyperplasia (UDH), ductal carcinoma in situ (DCIS) and IBC in 29 lesions of known PIK3CA genotype from 10 human breast specimens using a hyperspectral-based multiplexed tissue imaging platform (MTIP) to simultaneously quantitate PI3K/MAPK pathway targets (pAKT473, pAKT308, pPRAS40, pS6, and pERK) in FFPE tissue, with single cell resolution. Results We found that breast lesional epithelia contained spatially heterogeneous patterns of PI3K pathway phosphoprotein signatures, even within microscopic areas of CCL, UDH, DCIS and IBC. Most lesions contained 3–12 unique phosphoprotein signatures within the same microscopic field. The dominant phosphoprotein signature for each lesion was not well-correlated with lesion genotype or lesion histology, yet samples from the same patient tended to group together. Further, 5 UDH/CCL lesions across different patients had a common phosphosignature at the epithelial-stromal interface (possible myoepithelial cells) that was distinct from both the adjacent lesional epithelium, and distinct from adjacent stroma. Conclusion We present the first spatial mapping of PI3K phosphoprotein networks in proliferative breast lesions, and demonstrate complex PI3K signaling heterogeneity that defies simple correlation between PIK3CA genotype and phosphosignal pattern.

show abstract

“…The links for which the posterior is shown in E are highlighted in red. (D) Data and posterior predictive for three of the epitopes used for the inference; the data is the 1-hr time point of the dataset of Korkola et al [42]. The previous two datasets are included in the inference as well.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to the data we generated here, we included a part of the dataset provided by Korkola et al [42] in the inference. They performed RPPA measurements of 15 breast cancer cell lines, treated with either lapatinib (250 nM), GSK690693 (250 nM), a combination of the two, or a DMSO control, at 8 time points from 30 minutes to 72 hours.…”

Section: External Datamentioning

confidence: 99%

“…The negative feedback in the AKT pathway could be achieved in several different ways, either through IRS1 or through SIN1. To further resolve which of these proteins mediates the feedback, we extended the model to explicitly include IRS1 as signaling molecule ( Figure 5C), and we incorporated information from the dataset of Korkola et al [42], who performed time-course RPPA measurements with a different panel of cell lines upon inhibitor treatment, including the AKT inhibitor GSK690693. We selected the 1 hour time point from their dataset as it is closest to the 50 minute inhibitor treatment (30 minute inhibitor pre-treatment plus 20 minute subsequent EGF stimulation) in our intervention dataset.…”

Section: Negative Feedback Is Likely To Be Active In the Akt Pathwaymentioning

confidence: 99%

See 1 more Smart Citation

Delineating feedback activity in the MAPK and AKT pathways using feedback-enabled Inference of Signaling Activity

Thijssen

Jastrzebski

Beijersbergen

et al. 2018

Preprint

View full text Add to dashboard Cite

An important aspect of cellular signaling networks is the existence of feedback mechanisms. However, due to the complexity of signaling networks, as well as the presence of multiple interrelated feedback events, it can be difficult to identify which signaling routes are active in any particular context. We have previously shown that Inference of Signaling Activity (ISA) can be a useful method to study steady-state oncogenic signaling across different cell lines and inhibitor treatments. However, ISA did not explicitly include feedback signaling events. Incorporating feedback will increase the complexity and computational cost of the model, and more data is likely to be needed to infer feedback activities. Here, we developed feedback-ISA (f-ISA), an extension of the ISA modeling approach which incorporates feedback signaling events. It also includes integrated batch correction in order to fit the models to multiple, independent datasets simultaneously. We find that the identifiability of feedback activities can be counterintuitive, which shows the importance of analyzing the full, joint uncertainty in model parameters. By iteratively adapting the model and including multiple datasets, including both steady state and intervention data, we constructed a model that can explain a large part of the phosphorylation levels of several signaling molecules in the MAPK and AKT pathways, across many breast cancer cell lines and across various conditions. The resulting model delineates which routes in the signaling network are likely to be active in each cell line and condition, given all of the data. Additionally, such models can indicate whether datasets agree with each other, and identify which parts of the data cannot be explained, thereby highlighting gaps in the current knowledge. We conclude that this modeling approach can be useful to quantitatively understand how complex cellular signaling networks behave across different cell lines and conditions.

show abstract

Decoupling of the PI3K Pathway via Mutation Necessitates Combinatorial Treatment in HER2+ Breast Cancer

Cited by 19 publications

References 34 publications

GRB7 dependent proliferation of basal‐like, HER‐2 positive human breast cancer cell lines is mediated in part by HER‐1 signaling

GRB7 dependent proliferation of basal‐like, HER‐2 positive human breast cancer cell lines is mediated in part by HER‐1 signaling

Multiplexed imaging reveals heterogeneity of PI3K/MAPK network signaling in breast lesions of known PIK3CA genotype

Delineating feedback activity in the MAPK and AKT pathways using feedback-enabled Inference of Signaling Activity

Contact Info

Product

Resources

About