It is now well known that tumor cells lacking BRCA1/2 are highly sensitive to DNA damaging agents like platinum derivatives, as a consequence of impaired genomic damage repair which is induced by different mean [
19,
23]. Platinum compounds, through adduct formation at the DNA produce DBS, are specifically active in tumors with HR impairment for BRCA1/2 lack of function [
24]. There is strong evidence from preclinical and clinical studies for a specific sensitivity of different BRCA1/2-related tumors to platinum derivatives. In 2003 our group has demonstrated a differential chemosensitivity profile
in vitro of BRCA1-mutated HCC1937 breast cancer cells with bi-allelic loss as compared to the derivative clone HCC1937
WT, where the BRCA1 expression has been reconstituted by transfection of a BRCA1 full length cDNA [
25]. This study led to the conclusion that HCC1937 are highly sensitive to Cisplatinum (CDDP) as compared to Estrogen Receptor expressing and BRCA1-competent MCF-7 and BRCA1-reconstituted HCC1937
WT. In the same work it was demonstrated that BRCA1-defective HCC1937 breast cancer cells were resistant to paclitaxel as compared to MCF-7 and HCC1937
WT cells. In a further study by our group a differential chemosensitivity of BRCA1-mutated HCC1937 human breast cancer cells to microtubule-interfering agents has been found [
26] Quinn et al. in a similar cell system, where BRCA1 was reconstituted by a retroviral vector containing the full length cDNA and compared to parental cells infected with empty vector, demonstrated that BRCA1 functions as a differential modulator of chemotherapy-induced apoptosis. [
27]. In a recent follow up study [
28], our group evaluated the
in vivo differential chemosensitivity of BRCA1-defective
versus BRCA1-reconstrituted xenografts in SCID mice. In this mouse model, we confirmed a differential and higher activity of CDDP against HCC1937 BRCA1-defective xenografts. Furthermore, we demonstrated a major difference in the whole gene expression profile by cDNA microarray. Specifically, we found reduced expression of ERCC1 and RRM1 in HCC1937
versus BRCA1-reconstitued parental cells. Importantly, these two genes have been demonstrated to correlate, in previous studies in lung cancer, to an impaired response to CDDP treatment and to improved survival in patients undergoing treatment with CDDP/gemcitabine [
29,
30]. In addition, we found increased expression of mRNAs for RAD52 and XRCC1, genes related to DNA damage recognition. These latter findings strongly suggest a compensatory response to the impaired DNA damage repair in BRCA1 defective cells.
All together these experimental observations suggest that sensitivity to platinum derivatives inversely correlates to sensitivity to paclitaxel in BRCA1-defective breast tumor cells. Quinn et al. [
31] have recently demonstrated a direct correlation between BRCA1 mRNA expression levels and overall survival in patients with ovarian cancer undergoing chemotherapy. These authors have shown that inhibition of BRCA1 expression in ovarian cancer cell lines increases cell sensitivity to platinum derivatives, while reduces the antitumor activity of taxanes. Subsequently they have evaluated BRCA1 mRNA expression in 70 tissue samples in sporadic ovarian tumors from patients which underwent treatment with platinum derivatives and they found that patients with low-intermediate levels of BRCA1 mRNA had a significantly better outcome in terms of overall survival (OS) as compared to high BRCA1 mRNA levels (57.2 months versus 18.2 months p = 0.0017). Finally high BRCA1 mRNA tumor carriers had a better survival if treated with taxanes even if statistical significance was not reached. It was concluded that BRCA1 mRNA expression levels correlate in sporadic ovarian cancer patients with OS and can be considered a predictive marker of treatment response. More recently the same authors have produced a systematic review [
32] on all published studies on this topic from 1990 to 2008 leading to the hypothesis of a possible role of BRCA1 as biomarker predictive of treatment response in hereditary and sporadic ovarian tumors. The authors conclude that the identification of a functional deficit in BRCA1 and in related pathways is likely to provide information on treatment efficacy. Finally, the same authors have provided evidence that BRCA1 protein expression may be a predictive marker of chemotherapy response in sporadic epithelial ovarian cancer. They found that BRCA1 protein expression is associated with a better outcome of platinum/taxane combination as compared with CDDP alone, while when BRCA1 protein was not detected CDDP alone was as effective as combination chemotherapy. These data indicate again that CDDP alone may be highly effective in the case of BRCA1 impairment [
33].
It is a common finding that human tumors highly sensitive to chemotherapy may become resistant [
34]. Recent studies have shown that even the increased sensitivity to CDDP or Poly ADP Ribose Polymerase (PARP) inhibitors (see below) produced by BRCA1/2 gene mutation is not a stable trait [
35]. Stacey Edwards et al have demonstrated that when pancreatic cells with BRCA2 inactivation become resistant to PARP inhibitors, novel BRCA2 isoforms were detected in the resistant line resulting from intragenic deletion of the c.6174delT mutation and restoration of the open reading-frame (ORF) [
36]. Similarly Wataru Sakai et al. reported that secondary mutations in BRCA2 might reconstitute resistance to CDDP and PARP inhibitors in BRCA2 mutated tumors and that similar molecular mechanisms should be involved in clinical resistance to CDDP by ovarian tumors as demonstrated on clinical specimens [
37].
All together these findings indicate that BRCA1/2 gene-mediated sensitivity to anticancer treatment can be reverted by escape mutations and that these important events must be taken in account for the design of novel therapeutic strategies in this specific setting.