Prognostic value of CtIP/RBBP8 expression in breast cancer

Abstract

CtIP/RBBP8 is a multifunctional protein involved in transcription, DNA replication, DNA repair by homologous recombination and the G1 and G2 checkpoints. Its multiple roles are controlled by its interaction with several specific factors, including the tumor suppressor proteins BRCA1 and retinoblastoma. Both its functions and interactors point to a putative oncogenic potential of CtIP/RBBP8 loss. However, CtIP/RBBP8 relevance in breast tumor appearance, development, and prognosis has yet to be established. We performed a retrospective analysis of CtIP/RBBP8 and RB1 levels by immunohistochemistry using 384 paraffin-embedded breast cancer biopsies obtained during tumor removal surgery. We have observed that low or no expression of CtIP/RBBP8 correlates with high-grade breast cancer and with nodal metastasis. Reduction on CtIP/RBBP8 is most common in hormone receptor (HR)-negative, HER2-positive, and basal-like tumors. We observed lower levels of RB1 on those tumors with reduced CtIP/RBBP8 levels. On luminal tumors, decreased but not absence of CtIP/RBBP8 levels correlate with increased disease-free survival when treated with a combination of hormone, radio, and chemo therapies.

Keywords: Breast cancer; CtIP/RBBP8; DNA repair; retinoblastoma.

Figure 1

CtIP/RBBP8 and retinoblastoma (RB1) expression in breast cancer biopsies. Paraffin-embedded breast cancer biopsies were immunostained with CtIP/RBBP8 or RB1 antibodies and stained with hematoxylin and eosin as described in the Patients and Methods section. A representative image of each cancer subtype is shown. In addition, the gradation of CtIP/RBBP8 and RB1 protein level can be observed from 2 (normal; left) to 0 (triple negative; right).

Figure 2

Disease-free survival and response to hormone therapy of patients in the cohort with respect to the CtIP/RBBP8 levels. (A) Overall representation of tumor relapse in all the patients of the cohort. Disease-free survival data were obtained from clinical records and plotted using the Kaplan–Meier method. The cohort was divided according to CtIP/RBBP8 levels as follows: level 2, normal expression (black line, n = 66); level 1, low expression (blue line, n = 102); level 0, no expression (red line, n = 128). (B) Kaplan–Meier representation of the time patients with luminal tumors treated with tamoxifen remained disease free. CtIP/RBBP8 levels: level 2, normal expression (black line, n = 10); level 1, low expression (blue line, n = 13); level 0, no expression (red line, n = 20). (C) Disease-free survival times in patients with luminal tumors treated with aromatase inhibitors. CtIP/RBBP8 levels: level 2, normal expression (black line, n = 25); level 1, low expression (blue line, n = 22); level 0, no expression (red line, n = 23). (D) Tumor relapse in patients with luminal tumors treated with a combination of tamoxifen and aromatase inhibitors. CtIP/RBBP8 levels: level 2, normal expression (black line, n = 14); level 1, low expression (blue line, n = 18); level 0, no expression (red line, n = 13).

Figure 3

Relationship between the CtIP/RBBP8 levels and the response to chemotherapy for luminal cancers. (A) Disease-free survival times in patients with luminal tumors not treated with chemotherapy. CtIP/RBBP8 levels: level 2, normal expression (black line, n = 14); level 1, low expression (blue line, n = 12); level 0, no expression, (red line, n = 14). (B) Tumor relapse in patients with luminal tumors treated with chemotherapy as an adjuvant. An asterisk represents statistically representative changes (P < 0.05). CtIP/RBBP8 levels: level 2, normal expression (black line, n = 20); level 1, low expression (blue line, n = 18); level 0, no expression (red line, n = 21). In both cases (A and B), patients were treated with radiotherapy and hormone therapy.