The Role Of GRIM-19 And Its Target Gene STAT-3 In The Carcinogenesis Of Breast Cancer

BackgroundBreast cancer is the most frequently diagnosed cancer and the leading cause of cancer death among females, accounting for 23% of the total cancer cases and 14% of the cancer deaths, comprising 17% of the total new cancer cases and 23% of the total cancer deaths. Breast cancer is now also the leading cause of cancer death among females in economically developing countries, a shift from the previous decade during which the most common cause of cancer death was cervical cancer. Gene associated with retinoid-IFN-induced mortality (GRIM) was recently discovered. GRIM-19 is expressed in multiple normal tissues, which plays a part in cell proliferation and apoptosis, suggesting that it might be a tumor suppressor gene. The decreased expression of GRIM-19 or the mutation of the gene location could cause abnormal proliferation and malignant transformation of cells. Signal stransducer and activator of sranscription (STAT-3) keeps activation in breast cancer and has an increased expression, which promotes the cells proliferation, progression and metastasis, immune escape, and inhibits tumor cell apoptosis. GRIM-19 was regarded as the negative factor of STAT-3. The expression of GRIM-19 and STAT-3 was studied in order to investigate the relationship and clinical significance of GRIM-19 and STAT-3.Methods64 breast cancer samples and 30 benign breast tissue samples were collected from General Surgery Department of Jinan Central Hospital affiliated to Shandong University from May 2008 to April 2010. Among these samples, there were 54 non-tri-negative specimens,10 tri-negative specimens. Clinical stage was determined according to UICC (1997) standard. The expression of GRIM-19 and STAT-3 in breast cancer tissue was studied by immunohistochemistry (IHC). The first antibody was polyclonal mouse anti-human antibody GRIM-19 (ab88094, Abeam,USA); mouse anti-human STAT-3 (ab32500, Abeam, USA); SP IHC set and DAB set were purchased from Maixin Company (Fujian, China). The IHC Score (S) was analyzed according to the positive proportion in 100-cell group (P) and extent of positive staining (E). P was determined based on the percent of positive cells. 0:<10%; 1:10%～25%; 2:>25%～50%; 3:>50%～100%. E was graded according to the extent of staining.0:colorless; 1:light brown; 2:dark brown. S=E multiple P. Negative:≤2; Positive:>2.Results1. GRIM-19 was expressed in 29.7%(19/64) of breast cancer samples, compared with 83.3% (25/30) of control group. There was a significant difference between them (p<0.01); STAT-3 was expressed in 85.9% (55/64) breast cancer samples, compared with 10.0% (3/30) positive rate in control group (p<0.01).2. GRIM-19 was more lowly expressed in triple-negative breast cancer than that in non-triple-negative group (p<0.05). There were no significant differences between the two groups in the respects of age, differentiation, lymph nodes metastasis, ER, PR, HER-2/neu, and the clinical pathologic parameters (p> 0.05)Conclusions1. GRIM-19 may play an important role in the carcinogenesis of breast cancer. The loss of GRIM expression could induce the breast cancer and promote the further development.2. The expression of STAT-3 was inversely correlated with that of GRIM-19 in breast cancer.3. The expression of GRIM-19 was decreased significantly in triple-negative breast cancer.