EZH2 and ALDH1 expression in ductal carcinoma in situ: complex association with recurrence and progression to invasive breast cancer

Abstract

The diagnosis of ductal carcinoma in situ (DCIS) is an increasingly common event due to widespread use of screening mammography. However, appropriate clinical management of DCIS is a major challenge in the absence of prognostic markers. Tumor-initiating cells may be particularly relevant for disease pathogenesis; therefore, two markers associated with such cells, EZH2 and ALDH1, were evaluated. A cohort of 248 DCIS patients was used to determine the association of EZH2 and ALDH1 with ipsilateral breast event, DCIS recurrence and progression to invasive breast cancer (IBC). In this cohort, high EZH2 expression was associated with the risk of an ipsilateral breast event and DCIS recurrence but not invasive progression. ALDH1 expression was observed in both the tumor and stromal compartment; however, in neither compartment were ALDH1 levels independently associated with evaluated study endpoints. Interestingly, the combination of high EZH2 with high epithelial ALDH1 was associated with disease progression. Therefore, ALDH1 within the DCIS lesion can add to the prognostic significance of EZH2, particularly in the context of risk of development of invasive disease.

Keywords: ALDH1; DCIS; EZH2; IBC; ductal carcinoma in situ; invasive breast cancer; prognostic markers; tumor-initiating cells.

Figure 1. EZH2 is associated with risk of IBE and DCIS recurrence: (A) Representative images of EZH2 expression in DCIS. (B) Kaplan-Meier analyses of EZH2 status relative to IBE in the cohort analyzed. (C) Kaplan-Meier analyses of EZH2 status relative to IBC recurrence in the cohort analyzed. (D) Kaplan-Meier analyses of EZH2 status relative to DCIS recurrence in the cohort analyzed.

Figure 2. ALDH1 expression within DCIS is not associated with clinical outcome in DCIS: (A) Representative images of ALDH1 expression in DCIS epithelia and stroma (B) Kaplan-Meier analyses of ALDH1 status relative to IBE in the cohort analyzed. (C) Kaplan-Meier analyses of EZH2 status relative to IBC recurrence in the cohort analyzed.

Figure 3. Stromal ALDH1 expression is not associated with clinical outcome in DCIS: (A) Kaplan-Meier analyses of ALDH1 status relative to IBE in the cohort analyzed. (B) Kaplan-Meier analyses of ALDH1 status relative to IBC recurrence in the cohort analyzed.

Figure 4. Coordinate EZH2/ALDH1 status is associated with clinical outcomes in DCIS: (A) Kaplan-Meier analyses of ALDH1/EZH2 status relative to IBE in the cohort analyzed. (B) Kaplan-Meier analyses of high EZH2/ALDH1 vs. all other groups relative to IBE in the cohort analyzed. (C) Kaplan-Meier analyses of ALDH1/EZH2 status relative to IBC in the cohort analyzed. (D) Kaplan-Meier analyses of high EZH2/ALDH1 vs. all other groups relative to IBC in the cohort analyzed. (E) Kaplan-Meier analyses of stromal ALDH1/EZH2 status relative to IBE in the cohort analyzed. (F) Kaplan-Meier analyses of stromal ALDH1/EZH2 vs. all other groups relative to IBE in the cohort analyzed.