'I get by with a little help from my friends': The role of stromal cells in the breast cancer chemoresistance mechanism

Breast cancer is the most common cancer that affects women worldwide, and in New Zealand accounts for 1/3 of new cancer cases. The tumour microenvironment (TME) has an important role in how breast cancer cells respond to chemotherapeutic stress. Mesenchymal stromal cells (MStCs), a component of the TME, have been shown to function in the development of breast cancer cell chemoresistance, promoting survival and more aggressive cancer cell phenotypes. The effect of co-culture on the 4T1 murine breast cancer cell response to chemotherapy has been explored with DNA-damaging therapies but was yet to be explored against other chemotherapeutic mechanisms.

Fluorescent-4T1 cells were co-cultured with compact bone-derived MStCs and treated with chemotherapies of differing modalities. Flow cytometry, microscopy and gene expression assays were used to assess the effect of co-culture on the 4T1 response to treatment with clinically relevant chemotherapy drugs. Fluorescent-4T1s had altered morphology, disrupted cell cycles, and decreased viability in response to drug treatment. MStCs had low positive expression of classical stromal markers and had reduced effects of chemotherapy compared to 4T1s. Co-culture with MStCs decreased the effect of drug on 4T1 viability, morphology and cell cycle progression. Increased contact between 4T1s and MStCs resulted in enhanced survival of 4T1 cells under chemotherapeutic stress.

These results indicated that drug efficacy is decreased when cancer cells are in co-culture with supporting cells of the TME, independent of the modality of chemotherapeutic stress. This emphasises the importance of the TME to the cancer cell stress response and begins to delve into potential mechanisms for this enhanced interaction. Future research should investigate candidates for inhibiting this interaction between stromal and cancer cells.