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Adipose stromal cells (ASCs) recruited by tumors contribute to the population of cancer-associated fibroblasts. ASCs have been reported to induce tumor growth and chemotherapy resistance. The effect of ASCs on metastasis has not been explored. Here, we investigated the role of ASCs in cancer aggressiveness and tested them as a therapy target. We show that ASCs promote the epithelial-mesenchymal transition and invasiveness of triple-negative breast cancer cells. In human cell lines derived from various types of breast tumors, ASCs suppressed cytotoxicity of cisplatin and paclitaxel. D-CAN, a proapoptotic peptide targeting ASC, suppressed spontaneous breast cancer lung metastases in a mouse allograft model when combined with cisplatin. Moreover, in a human breast cancer xenograft model, treatment with D-CAN alone was sufficient to suppress lung metastases. This study improves our understanding of how tumor stromal cells recruited from fat tissue stimulate carcinoma progression to chemotherapy resistance/metastasis and outlines a new approach to combination cancer treatment.

The original algorithm that classified triple-negative breast cancer (TNBC) into six subtypes has recently been revised. The revised algorithm (TNBCtype-IM) classifies TNBC into five subtypes and a modifier based on immunological (IM) signatures. The molecular signature may differ between cancer cells in vitro and their respective tumor xenografts. We identified cell lines with concordant molecular subtypes regardless of classification algorithm or analysis of cells in vitro or in vivo, to establish a panel of clinically relevant molecularly stable TNBC models for translational research. Gene expression data were used to classify TNBC cell lines using the original and the revised algorithms. Tumor xenografts were established from 17 cell lines and subjected to gene expression profiling with the original 2188-gene algorithm TNBCtype and the revised 101-gene algorithm TNBCtype-IM. A total of six cell lines (SUM149PT (BL2), HCC1806 (BL2), SUM149PT (BL2), BT549 (M), MDA-MB-453 (LAR), and HCC2157 (BL1)) maintained their subtype classification between in vitro and tumor xenograft analyses across both algorithms. For TNBC molecular classification-guided translational research, we recommend using these TNBC cell lines with stable molecular subtypes.

Triple-negative breast cancer (TNBC) is a heterogeneous group of estrogen, progesterone, and HER2-negative breast cancers with poor clinical outcomes. The imipridone ONC201 is a G-protein-coupled dopamine receptor D2 modulator and an allosteric agonist of the mitochondrial protease caseinolytic protease P(ClpP), which induces apoptosis. Here, we aimed to develop a novel ONC201-based combination therapy targeting TNBC. We performed a reverse-phase protein array analysis of ONC201-treated/-untreated and -sensitive/-resistant cell lines to identify potential predictive biomarkers. A principal component analysis using measured protein expression levels, the apoptosis score (AS), and heatmaps of all the measured protein and AS-related protein expression levels did not show a clear correlation between the expression levels of a specific protein and ONC201 efficacy. Three-dimensional RNA interference kinome-wide library screening revealed the MAPK and PI3K/Akt pathways as potential synergistic therapeutic partners. The combination with the MEK inhibitor trametinib successfully inhibited the growth of both ONC201-sensitive/-resistant TNBC cell lines. The baseline ClpP level correlated with the efficacy of single-agent ONC201. Single and combination therapy increased caspase 3/7 activity. The predictive biomarkers and a detailed mechanism of synergy beyond an induction of caspase activation should be tested for translation into future studies.

Human epidermal growth factor receptor (EGFR) 2 (HER2) is overexpressed/amplified in about 25% of all breast cancers, and EGFR is overexpressed in up to 76% and amplified in up to 24% of triple-negative breast cancers (TNBC). Here, we aimed to identify inhibitors that may enhance the anti-tumor activity of neratinib for HER2+ breast cancer and TNBC. By conducting a non-biased high-throughput RNA interference screening, we identified PI3K/AKT/mTOR and MAPK as two potential inhibitory synergistic canonical pathways. We confirmed that everolimus (mTOR inhibitor) and trametinib (MEK inhibitor) enhances combinatorial anti-proliferative effects with neratinib under anchorage-independent growth conditions (p < 0.05). Compared to single agent neratinib, the combination therapies significantly enhanced tumor growth inhibition in both SUM190 HER2+ breast cancer (neratinib plus everolimus, 77%; neratinib plus trametinib, 77%; p < 0.0001) and SUM149 TNBC (neratinib plus everolimus, 71%; neratinib plus trametinib, 81%; p < 0.0001) xenograft models. Compared to single-agent neratinib, everolimus, or trametinib, both everolimus plus neratinib and trametinib plus neratinib significantly suppressed proliferation marker Ki67 and enhanced antitumor efficacy by activating the apoptosis pathway shown by increased Bim and cleaved-PARP expression. Taken together, our data justify new neratinib-based combinations for both HER2+ breast cancer and TNBC.