p66ShcA Promotes Breast Cancer Plasticity by Inducing an Epithelial-to-Mesenchymal Transition

Hudson, Jesse; Ha, Jacqueline R.; Sabourin, Valérie; Ahn, Ryuhjin; Selva, Rachel La; Livingstone, Julie; Podmore, Lauren; Knight, Jennifer F.; Forrest, Laura; Beauchemin, Nicole; Hallett, Michael; Park, Morag; Ursini‐Siegel, Josie

doi:10.1128/mcb.00341-14

Cited by 20 publications

(28 citation statements)

References 46 publications

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“…We examined whether the ability of p66ShcA to induce an EMT was associated with an increased lungmetastatic potential. Consistent with our published studies [23], p66ShcA increases Vimentin expression in ErbB2+ luminal breast tumors (NIC) whereas E-Cadherin levels are largely unaffected compared to control tumors (Additional file 7: Figure S7). Despite this fact, we observed no differences in the lungmetastatic potential of VC-or p66ShcA-expressing NIC tumors (Additional file 1: Figure S1E).…”

Section: Non-mitochondrial P66shca Pools Potentiate the Later Stages supporting

confidence: 90%

“…Even though p66ShcA induces an EMT in NIC tumors, which are models for luminal breast cancer [23], our data suggest that a p66ShcA-induced EMT is not sufficient to further promote lung metastasis of NIC tumors. Moreover, we do not observe differences Fig.…”

Section: Discussionmentioning

confidence: 63%

“…Furthermore, p66ShcA activates the Arf6 monomeric G protein in breast cancer cells to potentiate Ras signaling [26]. We recently demonstrated that p66ShcA induces an EMT in breast cancer cells [23]. Finally, a unique role for p66ShcA in hypoxia survival and the acquisition of stem-like features has been described in breast cancer cells [27].…”

Section: Introductionmentioning

confidence: 99%

“…For example, p66ShcA overexpression increases the proliferative rate of ovarian and prostate cancers [20,22]. Moreover, p66ShcA increases the migratory properties of prostate and breast cancer cells [1,23,24] by its recruitment to focal adhesion complexes, thereby regulating Rac1-mediated actin remodeling [16,25]. Furthermore, p66ShcA activates the Arf6 monomeric G protein in breast cancer cells to potentiate Ras signaling [26].…”

Section: Introductionmentioning

confidence: 99%

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p66ShcA functions as a contextual promoter of breast cancer metastasis

et al. 2020

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Background: The p66ShcA redox protein is the longest isoform of the Shc1 gene and is variably expressed in breast cancers. In response to a variety of stress stimuli, p66ShcA becomes phosphorylated on serine 36, which allows it to translocate from the cytoplasm to the mitochondria where it stimulates the formation of reactive oxygen species (ROS). Conflicting studies suggest both pro-and anti-tumorigenic functions for p66ShcA, which prompted us to examine the contribution of tumor cell-intrinsic functions of p66ShcA during breast cancer metastasis. Methods: We tested whether p66ShcA impacts the lung-metastatic ability of breast cancer cells. Breast cancer cells characteristic of the ErbB2+/luminal (NIC) or basal (4T1) subtypes were engineered to overexpress p66ShcA. In addition, lung-metastatic 4T1 variants (4T1-537) were engineered to lack endogenous p66ShcA via Crispr/Cas9 genomic editing. p66ShcA null cells were then reconstituted with wild-type p66ShcA or a mutant (S36A) that cannot translocate to the mitochondria, thereby lacking the ability to stimulate mitochondrial-dependent ROS production. These cells were tested for their ability to form spontaneous metastases from the primary site or seed and colonize the lung in experimental (tail vein) metastasis assays. These cells were further characterized with respect to their migration rates, focal adhesion dynamics, and resistance to anoikis in vitro. Finally, their ability to survive in circulation and seed the lungs of mice was assessed in vivo. Results: We show that p66ShcA increases the lung-metastatic potential of breast cancer cells by augmenting their ability to navigate each stage of the metastatic cascade. A non-phosphorylatable p66ShcA-S36A mutant, which cannot translocate to the mitochondria, still potentiated breast cancer cell migration, lung colonization, and growth of secondary lung metastases. However, breast cancer cell survival in the circulation uniquely required an intact p66ShcA S36 phosphorylation site. Conclusion: This study provides the first evidence that both mitochondrial and non-mitochondrial p66ShcA pools collaborate in breast cancer cells to promote their maximal metastatic fitness.

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Section: Non-mitochondrial P66shca Pools Potentiate the Later Stages supporting

confidence: 90%

Section: Discussionmentioning

confidence: 63%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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p66ShcA functions as a contextual promoter of breast cancer metastasis

et al. 2020

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“…However, one report suggests that the association between high p66ShcA levels and good outcome is reflective of the fact that p66ShcA is enriched in luminal breast cancers which have a better prognosis than other subsets [177]. This suggests that p66Shc enhances signaling downstream of the Met RTK and that Mets activation is required for p66Shc to induce epithelia-mesenchymal transition in luminal breast cancer.…”

Section: Model Of Shcmentioning

confidence: 99%

Role of ESR Pathway Genes in Breast Cancer: A Review

Kumar¹,

Myers²,

Homsi³

et al. 2018

ABCR

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Breast cancer is the leading cause of death in women. Prognosis of breast cancer is often pessimistic because the tumors are prone to metastasizing to the bone, brain, and lung. The estrogen signaling receptor (ESR) pathway contains 39 main genes and proteins which makes it one of the larger signaling pathways. Predominately this pathway and the proteins within are involved in breast growth and development, making it a prospective area of study for breast cancer. While the healthy ESR pathway has been constructed and is well established, a mechanistic model of mutated genes of ESR pathway has not been delved upon. Such mutated models could be utilized for selecting combinational targets for drug therapies, as well as elucidating crosstalk between other pathways and feedback mechanisms. To construct the mutated models of the ESR pathway it is imperative to assess what is currently understood in the literature and what inconsistencies exist in order to resolve them. Without this information, a model of the ESR pathway will be unreliable and likely unproductive. This review is the detailed literature survey of the biological studies performed on ESR pathways genes, and their respective roles in breast cancer. Furthermore, the details mentioned in the review can be beneficial for the integrated study of the ESR pathway genes, which includes, structural and dynamics study of the genes products, to have a holistic understanding of the cancer mechanism.

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Network Analysis Reveals a Signaling Regulatory Loop in the PIK3CA-Mutated Breast Cancer Predicting Survival Outcome

McGee

Tibiche

Trifiro

et al. 2017

Genomics, Proteomics &Amp; Bioinformatics

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Mutated genes are rarely common even in the same pathological type between cancer patients and as such, it has been very challenging to interpret genome sequencing data and difficult to predict clinical outcomes. PIK3CA is one of a few genes whose mutations are relatively popular in tumors. For example, more than 46.6% of luminal-A breast cancer samples have PIK3CA mutated, whereas only 35.5% of all breast cancer samples contain PIK3CA mutations. To understand the function of PIK3CA mutations in luminal A breast cancer, we applied our recently-proposed Cancer Hallmark Network Framework to investigate the network motifs in the PIK3CA-mutated luminal A tumors. We found that more than 70% of the PIK3CA-mutated luminal A tumors contain a positive regulatory loop where a master regulator (PDGF-D), a second regulator (FLT1) and an output node (SHC1) work together. Importantly, we found the luminal A breast cancer patients harboring the PIK3CA mutation and this positive regulatory loop in their tumors have significantly longer survival than those harboring PIK3CA mutation only in their tumors. These findings suggest that the underlying molecular mechanism of PIK3CA mutations in luminal A patients can participate in a positive regulatory loop, and furthermore the positive regulatory loop (PDGF-D/FLT1/SHC1) has a predictive power for the survival of the PIK3CA-mutated luminal A patients.

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p66ShcA Promotes Breast Cancer Plasticity by Inducing an Epithelial-to-Mesenchymal Transition

Cited by 20 publications

References 46 publications

p66ShcA functions as a contextual promoter of breast cancer metastasis

p66ShcA functions as a contextual promoter of breast cancer metastasis

Role of ESR Pathway Genes in Breast Cancer: A Review

Network Analysis Reveals a Signaling Regulatory Loop in the PIK3CA-Mutated Breast Cancer Predicting Survival Outcome

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