Guler Gulnur, Uner Aysegul, Guler Nilufer, Han Shuang-Yin, Iliopoulos Dimitrios, Hauck Walter W, McCue Peter, Huebner Kay
Department of Pathology, Hacettepe University, Ankara, Turkey.
Cancer. 2004 Apr 15;100(8):1605-14. doi: 10.1002/cncr.20137.
FHIT and WWOX are a tumor suppressor and a candidate suppressor that encompass the FRA3B and FRA16D fragile sites at chromosomes 3p14.2 and 16q23.3-24.1, respectively. Reduced or absent Fhit expression has been reported in two-thirds of invasive breast tumors in association with adverse prognostic factors. Loss of 16q has been reported frequently in low-grade, invasive breast tumors.
Expression of Fhit and Wwox was evaluated by immunohistochemical staining in 97 archived breast carcinoma specimens. Expression levels were analyzed for correlations with each other, as well as with various patient and tumor characteristics.
Reduced Fhit and Wwox expression in tumors was observed in 54.6% and 63.2% of specimens, respectively. Fhit and Wwox expression were correlated strongly (P = 0.001). Reduced Fhit staining was seen more frequently in premenopausal patients (P = 0.010), estrogen receptor (ER)-negative or scantly ER-positive tumors (P = 0.058 borderline), high-grade tumors (P = 0.005), and tumors with metastases (P = 0.041). Reduced Wwox staining was more common in tumors with less favorable ER status (P = 0.033). Wwox expression in normal tissue was reduced in 32.9% of specimens, especially in patients with higher stage disease (P = 0.033). Severely reduced Wwox staining (extent < 10%) in normal tissue was found only in postmenopausal women, but reduced Wwox staining (11-75%) was more common in premenopausal women (P = 0.012). Tumor status, lymph node status, and intensity of Fhit expression in tumors were related independently to survival (P = 0.003, P < 0.001, and P = 0.046, respectively).
The strong correlation observed between Fhit and Wwox expression was consistent with the common elevated susceptibility of fragile sites to DNA damage. Reduced Fhit expression is associated with adverse prognostic factors. The current results suggest that Wwox also has an important and complex association with steroid hormone expression and breast carcinogenesis.
FHIT和WWOX分别是一种肿瘤抑制基因和一个候选抑制基因，它们分别包含位于染色体3p14.2和16q23.3 - 24.1的FRA3B和FRA16D脆性位点。据报道，在三分之二的浸润性乳腺癌中，Fhit表达降低或缺失，并伴有不良预后因素。16q缺失在低级别浸润性乳腺癌中也经常被报道。
通过免疫组织化学染色对97份存档乳腺癌标本中的Fhit和Wwox表达进行评估。分析表达水平之间的相关性，以及与各种患者和肿瘤特征的相关性。
分别在54.6%和63.2%的标本中观察到肿瘤中Fhit和Wwox表达降低。Fhit和Wwox表达呈强相关性（P = 0.001）。Fhit染色降低在绝经前患者中更常见（P = 0.010），雌激素受体（ER）阴性或ER弱阳性肿瘤（临界值P = 0.058）、高级别肿瘤（P = 0.005）以及有转移的肿瘤（P = 0.041）中更常见。Wwox染色降低在ER状态较差的肿瘤中更常见（P = 0.033）。32.9%的标本中正常组织的Wwox表达降低，尤其是在疾病分期较高的患者中（P = 0.033）。仅在绝经后女性中发现正常组织中Wwox染色严重降低（范围<10%），但Wwox染色降低（11 - 75%）在绝经前女性中更常见（P = 0.012）。肿瘤状态、淋巴结状态以及肿瘤中Fhit表达强度与生存独立相关（分别为P = 0.003、P < 0.001和P = 0.046）。
Fhit和Wwox表达之间观察到的强相关性与脆性位点对DNA损伤的普遍易感性升高一致。Fhit表达降低与不良预后因素相关。目前的结果表明，Wwox也与类固醇激素表达和乳腺癌发生有着重要而复杂的关联。
