Clinicopathological significance of CD133 and CD44 expression in infiltrating ductal carcinoma and their relationship to angiogenesis

Abstract

Background: Breast cancer is the leading cause of cancer death in females worldwide, and the majority type is infiltrating ductal carcinoma (IDC). Most of IDC patients died of metastasis and recurrence. Cancer stem cells (CSCs) are defined with the ability to be self-renewal and potentially promote proliferation and formation of tumors. CSCs are related to angiogenesis and are important targets in new cancer treatment strategies. In this study, we purposed to investigate on expression and clinical significances of CSCs marked by CD133 and CD44 in IDC and their relationship to angiogenesis.

Methods: The specimens of IDC from 325 Chinese patients with follow-up were analyzed for CD133, CD44, CD82, and CD34 protein expression by immunohistochemical staining. The Pearson chi-square test and t test were used to assess the associations among the positive staining of these markers and clinicopathological characteristics. Postoperative overall survival time in these patients with IDC was analyzed by univariate and multivariate analyses.

Results: In IDC tissues, positive rates of 48.6%, 53.8%, and 42.2% were obtained for CD133, CD44, and CD82 protein, respectively; the mean score of microvessel density (MVD) was 20.5 ± 7.0 in IDC group. And there was a significant difference between the two groups. There was a positive relationship between the expression of CD133, CD44, and the score of MVD and the grades of tumor, lymph node metastasis, tumor-node-metastasis (TNM) stages (all P < 0.05); and the expression of CD82 was negatively related to grades of tumor, lymph node metastasis, and TNM stages (all P < 0.05). The overall mean survival time of the patients with CD133, CD44, and the score of MVD (≥21) positive expression was lower than that of patients with negative expression. The overall mean survival time of patients of CD82-positive expression was longer than that of patients of the negative expression group. The positive expression of CD133 and CD82, and TNM stages were independent prognostic factors of IDC (P < 0.05).

Conclusions: CSCs, angiogenesis, and aberrant expression of CD82 may be involved in the initiation, development, metastasis, and recurrence. It is suggested that CSCs, angiogenesis, and CD82 be possible as a therapeutic marker for anti-tumor therapy.

Figure 1

Expressions of CD133, CD44, and CD82 proteins. (A) Expression of CD133 protein in infiltrating ductal carcinoma. CD133 was expressed as positive in the membrane and cytoplasm of cancer cells (intensity of positivity: strong = 3, percentage of positive cells: >75% = 4, final score = 12, CD133 × 400, G 2). (B) Expression of CD44 protein in IDC. CD44 was expressed as positive in the membrane and cytoplasm of cancer cells (intensity of positivity: strong = 3, percentage of positive cells: >75% = 4, final score = 12, CD44 × 400, G 2). (C) Expression of CD82 protein in IDC. CD82 was expressed as positive in the membrane and cytoplasm of cancer cells (intensity of positivity: moderately = 2, percentage of positive cells: >75% = 4, final score = 8, CD82 × 400, G 2).

Figure 2

Kaplan-Meier survival analysis by CD133, CD44, MVD, and CD82 statuses. (A) Kaplan-Meier survival analysis by CD133 status (n = 325). Mean overall survival (OS) time was 46.8 months for the CD133-positive group and 57.9 months for the CD133-negative group (log rank = 16.243, P < 0.001). (B) Kaplan-Meier survival analysis by CD44 status (n = 325). Mean OS time was 48.7 months for the CD44-positive group and 57.0 months for the CD44-negative group (log rank = 5.340, P = 0.021). (C) Kaplan-Meier survival analysis by MVD status (n = 325). Mean OS time was 48.4 months for the MVD ≥21 group and 57.0 months for the MVD <21 group (log rank = 9.623, P = 0.002). (D) Kaplan-Meier survival analysis by CD82 status (n = 325). Mean OS time was 60.8 months for the CD82-positive group and 46.5 months for the CD82-negative group (log rank = 23.644, P < 0.001).