Oncogenic Role of Skp2 and p27^(Kip1) in Intraductal Proliferative Lesions of the Breast

Objective To investigate whether the connection of p27 Kip1 to S-phase kinase-associated protein 2 (Skp2) plays an oncogenic role in intraductal proliferative lesions of the breast. Methods Here we investigated the mechanism involved in association of Skp2's degradation of p27 Kip1 with the breast carcinogenesis by immunohistochemical method through detection of Skp2 and p27 Kip1 protein levels in 120 paraffin-embedded tissues of intraductal proliferative lesions including usual ductal hyperplasia (UDH, n=30), atypical ductal hyperplasia (n=30), flat epithelial atypia (FEA, n=30), and ductal carcinoma in situ (DCIS, n=30). Moreover, the expression status of Skp2 and p27 Kip1 in 30 cases of the normal breast paraffin-embedded tissues were explored. Results The DCIS group was with the highest Skp2 level and the lowest p27 Kip1 level, and the UDH group was with the lowest Skp2 level and the highest p27 Kip1 level. Both Skp2 and p27 Kip1 levels in the DCIS group were significantly different from those in the UDH group (all P<0.01). The levels of Skp2 and p27 Kip1 in the FEA group were significantly different from both the DCIS and UDH groups (all P<0.05). p27 Kip1 was negatively correlated with Skp2 in both the UDH group (r=-0.629, P=0.026) and DCIS group (r=-0.893, P=0.000). Conclusion Overexpression of Skp2 might be the mechanism underlying p27 Kip1 over degradation.

Clinical and pathological characteristics of intraductal proliferative lesions and coexist with invasive ductal carcinomas

Objective： The purpose of this study was to study the clinical and pathological characteristics of breast intraductal proliferative lesions （IDPLs） and associated with invasive breast cancer. Methods： We reviewed 327 cases of breast intra- ductal proliferative lesions including 53 cases of usual ductal hyperplasia, 57 cases of atypical ductal hyperplasia, 89 cases of ductal carcinoma in situ, and 128 cases coexist with invasive ductal carcinomas. Cases of pure invasive cancer without intraductal proliferative lesions were excluded. The mult IDPLs biological parameters including the express of ER, PR, HER2, HIF-lo and Ki-67 detected by immunohistochemistry S-P method （n = 327） and the levels of CA153, TSGF, CA125 and CEA both in nipple discharge and serum （n = 179） measured with Electrochemiluminescence method and their relationship were studied, and 30 cases of normal pregnant women were compared with. Results： A single histologic subtype was present in 49.85% （163/327） of the cases, two subtypes in 33.03% （108/327）, and three in 17.13% （56/327）. The most common subtypes present were cribriform （43.12%, 141/327） and solid （38.53%, 126/327）, while the comedo （16.35%, 54/327）, and micropapillary （12.84%, 42/327） subtypes were less common. Comedo and solid were frequently found together for coexpres- sion as were micropapillary and papillary subtypes. However, Comedo subtype was much less likely to be found with papillary, cribriform or micropapillary subtypes. Additionally, comedo subtypes tend to be hormone receptor negative, Her2 positive and high-grade while the cribriform and solid subtype tends to be hormone receptor positive, Her2 negative and low grade. Papil- lary subtype was least likely to be associated with an invasive cancer. Furthermore, the nipple discharge and serum levels of CA153, TSGF, CA125 and CEA in coexist with invasive ductal carcinomas patients were significantly higher than those in the benign breast disease （pure intraductal proliferative lesions） and normal pregnant women （P 〈 0.01）. Additionally, the levels of CA153, TSGF, CA125 and CEA in nipple discharge were significantly higher than in the serum （P 〈 0.01）, and had a positive correlation with the Ki-67, grade, clinical stage, lymph node metastasis and tumor recurrence （P 〈 0.05）, and negative correla- tion with the level of ER and PR （P 〈 0.05）. The sensitivity of the four serum tumor markers in combination was only 69.77%, in contrast, the combined detection both in discharge and serum was 97.67%, and the negative predictive value was 99.03%. The sensitivity of combined detection both in nipple discharge and serum were significantly higher than other detection （P 〈 0.05）. Conclusion： IDPLs often present more than one histologic subtype and the most common subtypes are cribriform and solid, while comedo and micropapillary subtypes are less common. Our results suggest that the levels of CA153, TSGF, CA125 and CEA in nipple discharge were significantly higher than those in the serum, and is associated with HIF-le. The aberration of HIF-la may play a key role during oncogenesis and promote breast cellular transformation into malignancy, a finding useful for further understanding of tumorigenesis. Nipple discharge can be the earliest presenting symptom of breast cancer. The dynamic combined detection of the four tumor markers both in nipple discharge and serum are helpful to the stratification of preoperative patients and benefit to better prewarning markers for monitoring their recurrence and metastasis and clinical staging of tumors in clinic, but cannot increase the sensitivity of judging the patients with early breast cancer.