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Purpose Molecular targeting is a powerful approach for aggressive claudin-low breast cancer (CLBC). Overexpression of PI3K catalytic subunit gamma (PIK3CG) in human CLBC is offering a promising opportunity for targeted therapies. We utilized a specific inhibitor of PIK3CG combined with paclitaxel (PTX) to treat CLBC cells in vitro and in vivo. Patients and methods The tumor cells growth and apoptosis in vitro were analyzed by CCK8, plate clone formation assay, tumorsphere assay, Hoechst staining and flow cytometry. The invasion and metastasis ability of tumor cells in vitro were investigated by wound healing and transwell experiments. Critical gene expression levels were checked by qRT-PCR and Western blot. Xenograft models with CLBC cell lines in SCID mice were established to investigate the effect of combined drugs in vivo. Results We identified that PIK3CG was a potential therapeutic target for CLBC patients. Targeting PIK3CG potentiated CLBC cells growth inhibition in 2D and 3D cultures by PTX. Inhibition of PIK3CG activation could enhance CLBC cells apoptosis and migration suppression induced by PTX. Manipulating autophagy was a validated approach for the use of PIK3CG inhibitor. Using CLBC xenograft mice model, we found that CLBC tumors in vivo could be well treated by combined drugs of PIK3CG inhibitor and PTX. Conclusion We demonstrated that PIK3CG was a potential target for the therapy of CLBC and inhibition of PIK3CG activation could reinforce the therapeutic effect of this aggressive disease by PTX. The combined use of PIK3CG inhibitor and PTX might be a potential regimen for treating this subtype of breast cancer.

Triple negative breast cancer (TNBC) accounts for 15–20% of breast carcinomas and represents one of the most aggressive forms of this disease. Basal and claudin-low are the two main molecular subtypes among TNBCs. We previously reported that deletion of Lfng in mouse mammary gland caused deregulated Notch activation and induced basal-like and claudin-low tumors with co-selection for Met amplification. In human breast cancers, the vast majority of basal tumors and a subset of claudin-low tumors show reduced Lfng expression. Elevated Met expression and activation is associated with basal as well as claudin-low subtypes. To examine roles of Met and Notch in TNBC cells, we established two cell lines that harbor Met amplification as well as Lfng deletion, and possess features of basal and claudin-low breast cancer subtypes. Pharmacological inhibition of Met not only suppressed cell growth, tumorsphere and colony formation, but also reversed epithelial-to-mesenchymal transition and inhibited cell migration in both cell lines. In contrast, inhibition of Notch signaling using a γ-secretase inhibitor (GSI) only suppressed colony formation. Interestingly, GSI had no effect as single agent, but exerted a synergistic effect with Met inhibitor, on cell growth in 2D culture. We found that inhibition of Met resulted in downregulation of Dll ligands and upregulation of Jagged ligands, leading to differential modulation of Notch signaling. Our results suggest that combination targeting of Met and Notch may prove beneficial for TNBC patients with Met overexpression and Notch hyperactivation.