Date Published: August 10, 2017
Publisher: Public Library of Science
Author(s): Flora Zagouri, Vassiliki Kotoula, George Kouvatseas, Maria Sotiropoulou, Triantafyllia Koletsa, Theofani Gavressea, Christos Valavanis, Helen Trihia, Mattheos Bobos, Georgios Lazaridis, Angelos Koutras, George Pentheroudakis, Pantelis Skarlos, Dimitrios Bafaloukos, Niki Arnogiannaki, Sofia Chrisafi, Christos Christodoulou, Pavlos Papakostas, Gerasimos Aravantinos, Paris Kosmidis, Charisios Karanikiotis, George Zografos, Christos Papadimitriou, George Fountzilas, Aamir Ahmad.
To evaluate the prognostic role of elaborate molecular clusters encompassing cyclin D1, cyclin E1, p21, p27 and p53 in the context of various breast cancer subtypes.
Cyclin E1, cyclin D1, p53, p21 and p27 were evaluated with immunohistochemistry in 1077 formalin-fixed paraffin-embedded tissues from breast cancer patients who had been treated within clinical trials. Jaccard distances were computed for the markers and the resulted matrix was used for conducting unsupervised hierarchical clustering, in order to identify distinct groups correlating with prognosis.
Luminal B and triple-negative (TNBC) tumors presented with the highest and lowest levels of cyclin D1 expression, respectively. By contrast, TNBC frequently expressed Cyclin E1, whereas ER-positive tumors did not. Absence of Cyclin D1 predicted for worse OS, while absence of Cyclin E1 for poorer DFS. The expression patterns of all examined proteins yielded 3 distinct clusters; (1) Cyclin D1 and/or E1 positive with moderate p21 expression; (2) Cyclin D1 and/or E1, and p27 positive, p53 protein negative; and, (3) Cyclin D1 or E1 positive, p53 positive, p21 and p27 negative or moderately positive. The 5-year DFS rates for clusters 1, 2 and 3 were 70.0%, 79.1%, 67.4% and OS 88.4%, 90.4%, 78.9%, respectively.
It seems that the expression of cell cycle regulators in the absence of p53 protein is associated with favorable prognosis in operable breast cancer.
The significance of cell cycle mediators in breast carcinogenesis is currently well established. Specifically, deregulation of crucial genes that control cell cycle checkpoints has been noted in various breast carcinomas . Moreover, dysfunction or loss of these genes can also mediate resistance to chemotherapeutic agents.
This study highlights the original concept of protein expression patterns with special prognostic relevance in the context of early breast cancer. Three clusters emerged from our elaborate analysis; the most favorable of them (cluster 2) was the one characterized by lack of p53 protein expression in parallel with the expression of the tumor suppressor protein p27. On the other hand, cluster 1, whose distinct feature pertained to the moderate expression of p21, did not seem to differ from the burdened cluster 3. The latter was characterized by the poor prognostic aspect of positive p53 status , often accompanied by negativity of the tumor suppressor proteins p21 and p27 . Of note, cyclin D1 and E1 both correlated with better outcome, either singly or clustered; this finding may seem counterintuitive as CCND1 is a weak oncogene, but is in line with earlier studies showing that over-expression of cyclin D1 is in fact associated with favorable outcomes in breast cancer, both in terms of prognosis and response to endocrine treatment [28, 29]. Interestingly enough, in a recently published meta-analysis, the impact of CCND1 expression on OS was a 1.67-fold increased risk for patients with ER-positive breast cancer; however, according to this meta-analysis, CCND1 overexpression does not impact the prognosis of patients with unselected primary breast cancer .