Abstract
Pathologic complete response (pCR) after neoadjuvant chemotherapy is considered a suitable surrogate marker of treatment efficacy in patients with triple-negative breast cancers (TNBCs). However, the molecular mechanisms underlying pCR as a result of such treatment remain obscure. Using real-time PCR arrays we compared the expression levels of 120 genes involved in the main mechanisms of DNA repair in 43 pretreatment biopsies of BRCA1-associated TNBCs exhibiting pCR and no pathological complete response (non-pCR) after neoadjuvant chemotherapy with cisplatin. Altogether, 25 genes were significantly differentially expressed between tumors exhibiting pCR and non-pCR, and these genes were downregulated in the pCR group compared to the non-pCR group. A difference in expression level greater than 1.5-fold was detected for nine genes: MGMT, ERCC4, FANCB, UBA1, XRCC5, XPA, XPC, PARP3, and RPA1. The non-homologous end joining and nucleotide excision repair pathways of DNA repair showed the most significant relevance. Expression profile of DNA repair genes associated with pCR was different in the node-positive (20 genes with fold change >1.5) and node-negative (only 3 genes) subgroups. Although BRCA1 germline mutations are the principal defects in BRCA1-associated TNBC, our results indicate that the additional downregulation of other genes engaged in major pathways of DNA repair may play a decisive role in the pathological response of these tumors to cisplatin neoadjuvant chemotherapy. The results suggest that patients with node-positive BRCA1-associated TNBCs that do not exhibit pCR after cisplatin neoadjuvant chemotherapy may be candidates for subsequent therapy with PARP inhibitors, whereas UBA1 may be a potential therapeutic target in node-negative subgroup.
Highlights
Triple-negative breast cancer (TNBC) is defined by the lack of immunohistochemical expression of the estrogen receptor (ER) and progesterone receptor (PR) and the absence of human epidermal growth factor receptor 2 (HER-2) overexpression
BRCA1 germline mutations are the principal defects in BRCA1-associated TNBC, our results indicate that the additional downregulation of other genes engaged in major pathways of DNA repair may play a decisive role in the pathological response of these tumors to cisplatin neoadjuvant chemotherapy
Deficiency in DNA damage repair is commonly found in many cancers [20, 21], it remains unclear whether and how this defect may influence the pathological response after cisplatin neoadjuvant chemotherapy in BRCA1-associated TNBCs
Summary
Triple-negative breast cancer (TNBC) is defined by the lack of immunohistochemical expression of the estrogen receptor (ER) and progesterone receptor (PR) and the absence of human epidermal growth factor receptor 2 (HER-2) overexpression. TNBC accounts for 15-20% of breast cancer cases [1]. TNBCs constitute approximately 80% of BRCA1-associated breast cancers [4]. TNBC is a heterogeneous disease so various TNBC subgroups may show differential responses to treatment [5] These tumors are known to be sensitive to inter-strand cross-linking agents, including platinum analogs because www.impactjournals.com/oncotarget they carry a defect in the DNA double-strand break (DSB) repair pathway. They are sensitive to poly(ADPribose) polymerase (PARP) inhibitors in the mechanism of synthetic lethality [6]
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