Interferon-dependant chemoresistance in breast cancer

Chemoresistance is a major obstacle in the treatment of primary and metastatic breast cancer
(BC). Identifying chemoresistance mechanisms utilised by cancer cells is therefore an
important step towards sensitising tumours to chemotherapy and improving treatment
outcomes. The Hughes group has recently identified an IFN-dependent resistance pathway in
claudin-low triple negative breast cancer (TNBC).
In this thesis, the relevance of IFN-dependent epirubicin resistance was assessed in multiple
BC cell lines representing claudin-low TNBC (MDA-MB-231), HER2-enriched (AU565), luminal
A (MCF-7) and luminal B (BT-474) BC through MTT and colony forming assays. The ability of
IFN to induce docetaxel resistance was also assessed. The effect of IFN on epirubicin-induced
DNA double stranded break formation was investigated in MDA-MB-231 through a γ-H2Ax
immunofluorescence assay. In addition, the clinical relevance of IFN signalling was assessed
in a cohort of 27 metastatic TNBC patients through immunohistochemical evaluation of IFNβ1
and MX1 expression in cancer and stromal cells.
Viability assays showed IFNα1 induced a dose-dependent epirubicin resistance in MDA-MB231 but did not induce resistance in AU565, MCF-7 or BT-474 cells. Moreover, IFN did not
induce resistance to docetaxel in any cell lines tested. In MDA-MB-231 cells, the addition of
IFNα1 significantly reduced epirubicin-induced expression of γ-H2Ax. Analysis of the cohort
of metastatic TNBC patients showed a significant correlation between IFNβ1 expression in
lymphocytes and MX1 expression in cancer cells, however this was not associated with
survival.
In conclusion, this thesis has shown IFN-dependent resistance to be subtype and
chemotherapy dependant in BC. Moreover, this thesis has identified paracrine IFN signalling
within the TNBC metastatic tumour microenvironment. Further study into the inhibition of
this pathway may lead to chemosensitising treatments and improved patient outcomes in
claudin-low TNBC. Additionally, investigation of the clinical relevance of this pathway in
metastatic BC should be performed using a larger cohort.