Nuclear MTA1 overexpression is associated with aggressive prostate cancer, recurrence and metastasis in African Americans

Abstract

Metastasis-associated protein 1 (MTA1), a negative epigenetic modifier, plays a critical role in prostate cancer (PCa) progression. We hypothesized that MTA1 overexpression in primary tumor tissues can predict PCa aggressiveness and metastasis. Immunohistochemical staining of MTA1 was done on archival PCa specimens from University of Mississippi Medical Center and University of Iowa. We found that nuclear MTA1 overexpression was positively correlated with the severity of disease progression reaching its highest levels in metastatic PCa. Nuclear MTA1 overexpression was significantly associated with Gleason > 7 tumors in African Americans but not in Caucasians. It was also a predictor of recurrent disease. We concluded that MTA1 nuclear overexpression may be a prognostic indicator and a future therapeutic target for aggressive PCa in African American men. Our findings may be useful for categorizing African American patients with a higher probability of recurrent disease and metastasis from those who are likely to remain metastasis-free.

Figure 1

(A): Nuclear MTA1 overexpression is associated with PCa progression from PIN to localized PCa to metastasis. Representative images of MTA1 expression and subcellular distribution in PCa tissues and metastatic lesions analyzed by IHC and accompanied by H&E staining are shown. Benign tissues and PIN showed weak or moderate staining mostly in the cytoplasm; meanwhile, nuclear staining was stronger with a greater Gleason score: mostly cytoplasmic in Gleason < 7 tumors, moderate cytoplasmic and nuclear in Gleason = 7 tumors; and predominantly nuclear staining in Gleason > 7 cases. Metastatic tissues showed strong, almost exclusively, nuclear staining. (B): Distribution of nuclear (N) to cytoplasmic (C) ratio (N/C ratio) of MTA1 staining (TS) in different PCa pathologic categories. Geometric mean for N/C ratio for each category was calculated. Differences in N/C ratio were statistically significant between localized PCa and PIN. N/C ratio in metastatic PCa was the highest since cytoplasmic staining was statistically decreased compared to other categories. N/C ratio in Gleason subgroups showed a tendency to increase with Gleason score but differences were not statistically significant (not shown).

Figure 2. Racial differences in nuclear MTA1 expression between African Americans and Caucasian Americans.

(A): Comparison of MTA1 nuclear staining in PIN, localized PCa and metastasis (left) and in Gleason subgroups (right) in whole cohort (WC). MTA1 nuclear overexpression is significantly higher in metastatic (MPCa) versus localized PCa (LPCa) and PIN. No statistically significant differences were found amongst Gleason subgroups. (B): Nuclear MTA1 overexpression in African American (AA) men is associated with disease progression and higher Gleason score. Differences in MTA1 nuclear expression were statistically significant between different pathologic categories (left) and between Gleason > 7 and Gleason < 7/Gleason = 7 (right). (C): Comparison of MTA1 nuclear staining in different pathologic categories (left) and in Gleason subgroups (right) in Caucasian Americans (CA). No statistically significant changes were found between MPCa and LPCa groups and between Gleason subgroups. Box plots represent each category/score, error bars show SEM, and horizontal lines represent median. TNS, total nuclear score.

Figure 3. Comparison of nuclear MTA1 overexpression in non-recurrent (NR) and recurrent (R) groups of PCa.

Expression levels of nuclear MTA1 positively correlate with the recurrent disease. WC, whole cohort; AA, African Americans; CA, Caucasian Americans.

Figure 4

(A): Subcellular localization and differential expression of MTA1 in cells representing different stages of PCa progression: RWPE1, “normal” immortalized prostate epithelial cells; LNCaP, androgen-responsive cells; Du145, androgen-resistant cells; PC3M, aggressive metastatic cells. (B): MTA1 nuclear expression in MDA PCa 2b cells derived from bone metastatic site of AA man is comparable with high levels of MTA1 in PC3M aggressive cell line. Nuclear and cytoplasmic fractions were obtained for western blot analysis. Erk and lamin A were used as loading controls for cytoplasmic and nuclear fractions, respectively. Full-length blots can be found in the Supplementary Information.