ShcD adaptor protein drives invasion of triple negative breast cancer cells by aberrant activation of EGFR signaling.

Triple-negative breast cancer (TNBC) is highly metastatic and presents clinical challenges given the lack of targeted therapies. Here, we report that the ShcD phosphotyrosine adaptor protein is upregulated in TNBC, and its expression correlates with overall reduced patient survival and decreased response to chemotherapy. In human breast cancer cells, we demonstrate that ShcD expression promotes cell invasion and reduces adhesion, and that these effects are abrogated by mutating the ShcD phosphotyrosine binding (PTB) domain. Similarly, in a three-dimensional assembloid model, ShcD-expressing spheroids derived from brain metastatic TNBC cells show enhanced infiltration into cerebral organoids. Using a proteomic screen for ShcD binding partners, we identify multiple components of epidermal growth factor receptor (EGFR) signaling and confirm these interactions with ShcD but not the PTB mutant. Interestingly, the ShcD interactome correlates with EGFR tyrosine kinase inhibitor resistance, in line with our findings that ShcD overexpression results in hyperphosphorylation of EGFR while ShcD knockout or PTB mutation reverts this response. Lastly, pharmacological inhibition of the ShcD PTB domain using indomethacin in TNBC cells decreases EGFR binding and hyperphosphorylation and reduces cell invasion. Altogether, our results identify ShcD as a potential contributor to metastasis in TNBC, and they provide a molecular basis for clinical targeting of adaptor proteins.