Elsevier

Human Pathology

Volume 44, Issue 10, October 2013, Pages 2180-2187
Human Pathology

Original contribution
Novel prognostic markers for patients with triple-negative breast cancer,☆☆

https://doi.org/10.1016/j.humpath.2013.03.021Get rights and content

Summary

Triple-negative breast cancer (TNBC) is a subtype of breast cancer characterized by poor prognosis. Currently, no reliable markers have been identified as having a predictive role for the prognosis of TNBC patients. In this study, 119 breast cancer samples, including 31 TNBC and 89 non-TNBC subtypes, were collected. The protein levels of cleaved caspase-3 (CC3), aldehyde dehydrogenase 1 (ALDH1), cyclooxygenase-2, Ki-67, H2A histone family member X, and phosphorylated protein kinase B protein were measured by immunohistochemical staining. The percentage of positive CC3 (P = .017), ALDH1 (P = .015), Ki-67 (P = .001), and H2A histone family member X (P = .016) staining was significantly higher in TNBC than in non-TNBC cases. Positive CC3 and ALDH1 staining significantly correlated with poor prognosis of breast cancer, the TNBC subtype and non-TNBC subtype. Positive cyclooxygenase-2 expression significantly correlated with the survival of patients with TNBC. Multivariate analysis demonstrated that CC3 and ALDH1 are independent prognostic factors for BC and non-TNBC. ALDH1 is a prognostic marker for TNBC patients.

Introduction

Breast cancer (BC) is the most common type of cancer and the second most common cause of cancer-related deaths in women in the United States. Despite numerous advances in prevention, surgical resection, and adjuvant radiotherapy and chemotherapy, about 450, 000 patients die of BC worldwide annually [1]. Approximately 15% to 17% of cases are triple-negative breast cancer (TNBC), a subtype characterized by tumors that do not express estrogen receptor (ER), progesterone receptor (PR), and HER2 genes. TNBC is an important clinical challenge because it does not respond well to endocrine therapy and there is no readily available, effective, and specific targeted therapy for TNBC [2]. Although TNBC is sensitive to chemotherapy, early relapse is more common in patients with TNBC than in patients with other subtypes of BC [1], [2]. These characteristics of TNBC highlight the urgent need for identification of novel biomarkers for TNBC subtyping, prognosis, and targeted therapy.

Currently, markers for targeted therapy show inconsistent results in BC therapy. Targeting agents that are currently being investigated include epidermal growth factor receptor, vascular endothelial growth factor, and poly(adenosine diphosphate ribose) polymerase inhibitors; but there is still a lack of consistent improvement in the survival of BC patients [1].

The predictive roles of aldehyde dehydrogenase 1 (ALDH1), cyclooxygenase-2 (Cox-2), Ki-67, and phosphorylated Akt (p-Akt) have been investigated in BC, with conflicting outcomes [3], [4], [5]. A possible cause for the conflicting findings among these studies is that BC was not stratified using the same subtyping standards. Particularly, aggressive TNBC was not studied separately from other, nonaggressive BCs. At present, a reliable prognostic marker of BC remains elusive; and studies looking for a reliable biomarker for TNBC prognosis and targeting therapy are rare.

In this study, we first examined ER, PR, and HER2 protein expression in 119 BCs to classify BCs into TNBC and non-TNBC subtypes. We then investigated cleaved caspase-3 (CC3), ALDH1, Ki-67, p-Akt, Cox-2, and H2A histone family member X (H2AX) protein expressions in TNBC compared with non-TNBC and analyzed their correlations with the overall survival of patients with BC, TNBC, and non-TNBC.

Section snippets

Ethics statement

This study was done ethically with preapproval from the Ethics Committee for Human Studies at Shanghai Jiaotong University and was carried out in accordance with the Declaration of Helsinki. Participants were fully informed about the measurements taken in the study. Written informed consent forms were obtained from all participants.

Case selection

A total of 119 BC samples were collected from January 2003 to December 2009 at First People's Hospital, Shanghai Jiaotong University. Among the 119 patients with BC,

Clinical characteristics and protein expressions between TNBC and non-TNBC subtypes

Among the 119 BCs, 31 (26%) were identified as TNBC (ER, PR, HER2), whereas 88 (74%) with at least 1 positive marker were classified as non-TNBC. In addition to histological grades, no significant difference was observed in age, tumor size, TNM staging, or lymph node metastasis between TNBC and non-TNBC groups (Table 1). Immunohistochemistry revealed that positive reactions for CC3, ALDH1, Cox-2, and p-Akt were mainly localized to the cytoplasm with some positive staining on the membrane,

Discussion

In this study, we demonstrated that the percentage of CC3, ALDH1, Ki-67, and H2AX expression detected by immunohistochemistry was significantly higher in TNBC tissues than that in non-TNBC tissues. However, only CC3 and ALDH1 levels significantly correlated with poor survival in TNBC, non-TNBC, and BC patients. In contrast, Cox-2 was strongly associated with poor prognosis of TNBC, although its positive percentage in TNBC was not higher than that in non-TNBC.

Recently, ALDH1 activity has been

References (20)

There are more references available in the full text version of this article.

Cited by (45)

  • DNA damage in obesity: Initiator, promoter and predictor of cancer

    2018, Mutation Research - Reviews in Mutation Research
    Citation Excerpt :

    Indeed, the suitability of gamma foci continues to be explored as a diagnostic and prognostic marker for cancer (Table 5). A higher frequency of γ-H2AX foci have been found expressed in breast cancer cells from the more aggressive triple negative breast cancer (TNBC) when compared to cells from non-TNBC [120]. Gamma foci have also been suggested as an appropriate diagnostic and prognostic marker for colon cancer [121] and more recently, epithelial ovarian cancer [122].

View all citing articles on Scopus

Funding: This project was supported by grants from the National Natural Science Foundation (81120108017, 81172030), the National Basic Research Program of China (2010CB529902), and the Shanghai Hongkou District Public Health Bureau (1001-01).

☆☆

Disclosure: All authors declared no conflict of interest.

1

These authors equally contribute to this work.

View full text