cancer-2018-posters-abstracts

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Journal of Medical Oncology and Therapeutics | Volume: 3

July 23-25, 2018 | Moscow, Russia

World Cancer Congress

The p

isoform of

Shc1

is a key driver of Breast Cancer initiation

Andrey Sorokin

Medical College of Wisconsin, USA

amilyofShcadaptorproteins(encodedbyShc1gene)consists

of three functionally distinct isoforms (p46Shc, p52Shc, and

p66Shc) that serve as intracellular adaptors for several key

signaling pathways in breast cancer. Despite the broad evidence

implicating Shc1 as a central mediator of breast cancer, testing

the isoform-specific roles of Shc1 have been inaccessible due

to the lack of isoform-specific inhibitors or gene knockout

models. Here, we addressed this issue by generating the first

isoform-specific gene knockout models for p52Shc and p66Shc,

using germline gene-editing in the SS rat strain. Compared

with the wild type (WT) rats, we found that genetic ablation of

the p52Shc isoform significantly attenuated mammary tumor

formation, whereas the p66Shc knockout had no effect. These

data, combined with p52Shc being the predominant isoform

that is upregulated in human and rat tumors, provide the

first evidence that p52Shc is the oncogenic isoform of Shc1 in

breast cancer. Compared with WT tumors, 893 differentially

expressed genes were detected in p52Shc KO tumors compared

with only 18 differentially expressed genes in the p66Shc

KO tumors, further highlighting that p52Shc is the relevant

Shc1 isoform in breast cancer. Finally, gene network analysis

revealed that p52Shc KO disrupted multiple key pathways that

have been previously implicated in breast cancer initiation

and progression, including ESR1, mTORC2/RICTOR, and STAT5.

Collectively, these data demonstrate the p52Shc isoform is the

key driver of DMBA-induced breast cancer while the expression

of p66Shc and p46Shc are not enough to compensate.