PARP-1 Expression and BRCA1 Mutations in Breast Cancer Patients’ CTCs

Abstract

BRCA1 and PARP are involved in DNA damage repair pathways. BRCA1 mutations have been linked to higher likelihood of triple negative breast cancer (TNBC). The aim of the study was to determine PARP-1 expression and BRCA1 mutations in circulating tumor cells (CTCs) of BC patients. Fifty patients were enrolled: 23 luminal and 27 TNBC. PARP expression in CTCs was identified by immunofluorescence. Genotyping was performed by PCR-Sanger sequencing in the same samples. PARP-1 expression was higher in luminal (61%) and early BC (54%), compared to TNBC (41%) and metastatic (33%) patients. In addition, PARP-1 distribution was mostly cytoplasmic in luminal patients (p = 0.024), whereas it was mostly nuclear in TNBC patients. In cytokeratin (CK)-positive patients, those with the CK+PARP+ phenotype had longer overall survival (OS, log-rank p = 0.046). Overall, nine mutations were detected; M1 and M2 were completely new and M4, M7 and M8 were characterized as pathogenic. M7 and M8 were predominantly found in metastatic TNBC patients (p = 0.014 and p = 0.002). Thus, PARP-1 expression and increased mutagenic burden in TNBC patients’ CTCs, could be used as an indicator to stratify patients regarding therapeutic approaches.

Genetic Heterogeneity, Tumor Microenvironment and Immunotherapy in Triple-Negative Breast Cancer

“…Another study found an overexpression of Poly(ADP-ribose) polymerase 1 ( PARP-1 ) enzyme in tissue of TNBC patients by RNA microarray, and this was validated by immunohistochemistry [ 28 ]. PARP-1 expression has also been detected in circulating tumor cells in blood plasma of breast cancer patients and could be used in prediction of therapy selection and patient outcome [ 29 ]. A separate study found that Basic Helix–Loop–Helix Family Member E41 ( BHLHE41 or SHARP1 ) is a key regulator of the invasive and metastatic phenotype of the most aggressive forms of TNBC .…”

Cancer Biomarkers in Liquid Biopsy for Early Detection of Breast Cancer: A Systematic Review

“…In total, 16 142 articles were identified in the aforementioned databases (Table 1). However, 234 articles were retained for full reading, following the elimination of duplicates and articles whose title and abstract did not meet the eligibility criteria; of these, only 136 12…”

Updates on Triple-Negative Breast Cancer in Type 2 Diabetes Mellitus Patients: From Risk Factors to Diagnosis, Biomarkers and Therapy

“…The circulating tumor cells (CTCs) represent another feature of biomarkers as these tumor cells have been detached from the primary tumor or even from metastatic tumors, shed into the vasculature or lymphatic system and found disseminated in the patient's blood circulation. Many studies have evidenced CTC presence in TNBC patients at different stages (i.e., early and metastatic settings) with the detection of enhanced nuclear PARP-1 activity and observed an increased enumeration of CTCs in a metastatic advanced stage of TNBC and a drop of CTC percentage after neoadjuvant chemotherapy [171,172]. At an early stage of breast cancer, CTCs can generate micrometastases and serve as surrogates for minimal residual disease (MRD).…”

“…Pivotal role in cell cycle arrest, apoptosis, DNA repair, and genomic integrity [201] Molecular regulation of several key metabolic regulators involved in lipid and glucose metabolism, glucose transporter [202] Loss of function mutation [36] TP53 mutations associated with worse outcomes in TNBC patients with residual disease following chemotherapy [207]. High expression of nuclear PARP-1 [172] Increasing of peripheral blood mononuclear cells (PBMCs) nuclear ADP-ribose, a surrogate of PARP activity, in uncontrolled glycemic cases [220] mTOR/ p70S6K1 Pathway Induction of protein synthesis, cell growth, survival, tumorigenesis, chemotherapeutic drug resistance [224] Crucial role in lipid production, inhibition of mTOR pathway promoting insulin resistance and metabolic alterations, including T2DM [222] mTOR pathway hyperactivated involved in TNBC survival and chemoresistance [223] Higher mTOR pathway activation in TNBC, associated with poor prognosis [225]…”