p66ShcA functions as a contextual promoter of breast cancer metastasis
Posted on 2020-01-16 - 04:56
Abstract 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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Lewis, Kyle; Kiepas, Alex; Hudson, Jesse; Senecal, Julien; Ha, Jacqueline; Voorand, Elena; et al. (2020). p66ShcA functions as a contextual promoter of breast cancer metastasis. figshare. Collection. https://doi.org/10.6084/m9.figshare.c.4819332.v1
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AUTHORS (20)
KL
Kyle Lewis
AK
Alex Kiepas
JH
Jesse Hudson
JS
Julien Senecal
JH
Jacqueline Ha
EV
Elena Voorand
MA
Matthew Annis
VS
Valerie Sabourin
RA
Ryuhjin Ahn
RS
Rachel Selva
ST
Sébastien Tabariès
BH
Brian Hsu
MS
Matthew Siegel
MD
Matthew Dankner
EC
Eduardo Canedo
ML
Mathieu Lajoie
IW
Ian Watson
CB
Claire Brown
PS
Peter Siegel
JU
Josie Ursini-Siegel