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Previously we identified MCPH1, a DNA damage response protein involved in the regulation of BRCA1 and BRCA2, as the defective protein in one form of microcephaly. BRCA1 mutations are associated with basal-like breast cancer, which are often also negative for oestrogen receptor (ER), progesterone receptor (PR) and HER2. Our data indicate that MCPH1 plays a role in response to chemotherapeutic agents used in the treatment of breast cancer due to its role in DNA repair and the spindle checkpoint.
MCPH1 immunohistochemistry was performed on 320 breast cancers and correlated with pathology, survival, ER, PR and HER2 data. Drug assays were performed on the breast cell lines MCF10A, MCF7 and HCC193 with different MCPH1 and BRCA1 backgrounds created using siRNA.
We identified reduced MCPH1 expression in 23% (74/320) of breast cancers. After performing continuous data analysis, the mean MCPH1 expression decreased with increasing grade, grade 1 and 2 versus grade 3 (P < 0.006). Interestingly, mean MCPH1 expression was also lower in ER/PR-negative (P < 0.001) and triple-negative cancers (P < 0.004). An association with HER2- positive cancers was also identified (P < 0.03). While no association with survival was identified initially, the longer term survival was better in patients with higher mean MCPH1 expression. Our cell line drug assays indicate that MCPH1 plays a role in resistance to Taxol and sensitivity to cisplatin and doxorubicin.
MCPH1 expression is reduced in 23% of breast cancers, particularly in higher grade tumours. Interestingly, reduced mean MCPH1 expression was associated with the triple-negative phenotype often seen in basal-like cancers. Further basal cell markers are currently under investigation. Aggressive basallike breast cancers have a poor prognosis; MCPH1 expression may potentially improve treatment of these cancers.
This work was supported by Breast Cancer Campaign and Yorkshire Cancer Research.