BRCA1 alterations with additional defects in DNA damage response genes may confer chemoresistance to BRCA‐like breast cancers treated with neoadjuvant chemotherapy

Abstract

The BRCA-like phenotype is a feature that some sporadic breast cancers share with those occurring in BRCA1 or BRCA2 mutation carriers. As tumors with the phenotype have defects in the DNA damage response pathway, which may increase sensitivity to drugs such as DNA cross-linking agents and PARP inhibitors, a method to identify this phenotype is important. The prediction of chemoresistance, which frequently develops in these tumors, is also crucial for improving therapy. We examined genomic aberrations and BRCA1 promoter methylation in tumors of 73 breast cancer (20 HR-/HER2- and 53 HR+/HER2-) patients, who received neoadjuvant chemotherapy with anthracycline, cyclophosphamide, and taxane, using SNP array CGH and quantitative PCR. The methylation and/or loss or uniparental disomy (UPD) of BRCA1 (BRCA1 alterations) and the loss or UPD of BRCA2 (BRCA2 alterations) were detected in 27 (37%) and 21 (29%), respectively, of the 73 tumors. Tumors with BRCA1 or BRCA2 alterations were associated with a higher number of genomic aberrations (P < 0.001 and P < 0.001) and higher percentage of TP53 alterations (P < 0.001 and P < 0.001) than those without. Overall survival (OS) rates were similar between patients with or without BRCA1 or BRCA2 alterations. However, when 27 patients with BRCA1-altered tumors were classified into those with or without the loss or UPD of PALB2, PAGR1, RAD51B, FANCM, MLL4, or ERCC1/2 in tumors, patients with additional defects in DNA damage response genes had worse OS (P = 0.037, 0.045, 0.038, 0.044, 0.041, or 0.019) than those without. These defects may confer chemoresistance and predict poor outcomes in patients with BRCA1-altered breast cancer.

Optimization Of Cancer Treatment Through Overcoming Drug Resistance

“…When BRCA1 is inactivated by mutations, deletions, or down-regulation, cancer cells will no longer be able to repair the drug-induced DNA damage and will therefore trigger apoptosis, which explains why loss of BRCA1 sensitizes cancer cells to DNA damaging agents such as cisplatin and PARP [poly (ADP-ribose) polymerase] inhibitors. Similar findings have been applied to basal-like breast cancer which is characterized by being triple negative and aggressive [ 42 – 44 ]. Defects in DNA repair is a promising therapeutic target as BRCA alterations are found in 11 to 42% of these tumors, with a frequency varying according to family history and ethnicity.…”

“…BRCA1 is frequently mutated in inherited breast and ovarian cancers though somatic mutations rarely reported in sporadic cases. Nevertheless, down-regulation of BRCA1 occurs more often with epigenetic modifications [ 42 ].…”

The RXFP3 receptor is functionally associated with cellular responses to oxidative stress and DNA damage

“…In contrast to these unique expression events, 12 proteins were significantly altered across all five RXFP3 expression levels (Supplementary Figure 3: PRR14L, SCYL1, CCDC9, NEK7, HIST1H3A, ATPIF1, CDCA2, PAGR1, POTEKP, MTMR1, ZCCHC3, MEPCE). Many of these commonly regulated proteins are known to be associated with energy balance regulation (PRR14L [40]), inflammaging (NEK7 [41]; ATPIF1 [42]), aging associated DNA damage (SCYL1 [43]; CCDC9 [44]; HIST1H3A [45]; ATPIF1 [46]; PAGR1 [47]; ZCCHC3 [48]) or cell senescence (CDCA2 [49]). As such it appears that in addition to expression level effects, a core functionality of the RXFP3 was also evident, which was tightly linked to age-related pathologies.…”

The Role of Tumor Microenvironment in Chemoresistance: To Survive, Keep Your Enemies Closer

“…Mechanisms that contribute to chemoresistance include tumor heterogeneity, drug inactivation, apoptosis evasion, enhanced deoxyribonucleic acid (DNA) repair, increased drug efflux, epithelial-to-mesenchymal transition and the involvement of the tumor microenvironment (TM) [ 8 ]. Though cancer cell chemoresistance is usually attributed to heterogeneity within the cancer cell population, mutations and epigenetic alterations influencing the metabolism and retention of drugs by cancer cells [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ], additional causes could play important roles in the development of this phenomenon. Most important is the diversity within the tumor microenvironment (TM) in terms of the stromal cells present, the amount of oxygen available and the acidity of the environment [ 18 , 19 , 20 , 21 , 22 , 23 , 24 ].…”

“…The genetic makeup of cancer cells and cellular processes occurring within cancer cells contribute immensely to the inability of most chemotherapeutic drugs used in clinical oncology to effectively clear these cells from the body [ 12 , 14 , 15 , 16 , 17 , 35 , 36 , 37 ]. Several mutations to key genes encoding important proteins responsible for xenobiotic metabolism, as well as import and export of drugs from cells such as the ABC transporters have been identified and shown to influence how tumor cells respond to several drugs [ 12 , 14 , 15 , 16 , 17 , 35 , 36 , 37 ]. However, with remarkable advancement in technology and analytical methods seen in the last decade, attention has shifted to the TM contribution towards the development of chemoresistance [ 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 ].…”