BACKGROUND: We had previously established that inactivation of RUNX3 occurs by frequent promoter hypermethylation and protein mislocalization in invasive ductal carcinomas (IDC) of breast. Here, we hypothesize that inactivation of RUNX3 occurring in ductal carcinoma in situ (DCIS) represent early event in breast carcinogenesis. METHODS: The study cohort of 40 patients included 17 pure DCIS cases and 23 cases of DCIS with associated IDC (DCIS-IDC). The DCIS and IDC components of mixed cases were manually microdissected to permit separate evaluation. All the 63 samples including 17 pure DCIS, 23 samples each of DCIS and IDC of DCIS-IDC cases were analyzed for RUNX3 protein expression using R3-6E9 monoclonal antibody as well as promoter methylation status by methylation specific PCR. RESULTS: Compared to matched normal breast samples (4 of 40, 10%), DCIS (35 of 40, 88%) and IDC (21 of 23, 91%) exhibited significant RUNX3 inactivation (P<0.001) in the form of negative or weak nuclear staining. In contrast to normal breast tissues (1/10, 10%), promoter hypermethylation of RUNX3 was significantly higher in the neoplastic breast samples (46 of total 61, 75%) including 30 of 40 (75%) DCIS and 16 of 21 (76%) IDC samples (P=0.009). Overall, promoter hypermethylation correlated with RUNX3 inactivation in 42 of 46 (91%) methylated samples (P=0.03). Mislocalized cytoplasmic expression also accounted for RUNX3 inactivation in majority of DCIS (33/40, 83%) and IDC (20/23, 87%) samples independent of promoter hypermethylation. CONCLUSION: Our data suggest that RUNX3 inactivation by promoter hypermethylation and protein mislocalization constitute an early event in breast cancer progression.
BACKGROUND: We had previously established that inactivation of RUNX3 occurs by frequent promoter hypermethylation and protein mislocalization in invasive ductal carcinomas (IDC) of breast. Here, we hypothesize that inactivation of RUNX3 occurring in ductal carcinoma in situ (DCIS) represent early event in breast carcinogenesis. METHODS: The study cohort of 40 patients included 17 pure DCIS cases and 23 cases of DCIS with associated IDC (DCIS-IDC). The DCIS and IDC components of mixed cases were manually microdissected to permit separate evaluation. All the 63 samples including 17 pure DCIS, 23 samples each of DCIS and IDC of DCIS-IDC cases were analyzed for RUNX3 protein expression using R3-6E9 monoclonal antibody as well as promoter methylation status by methylation specific PCR. RESULTS: Compared to matched normal breast samples (4 of 40, 10%), DCIS (35 of 40, 88%) and IDC (21 of 23, 91%) exhibited significant RUNX3 inactivation (P<0.001) in the form of negative or weak nuclear staining. In contrast to normal breast tissues (1/10, 10%), promoter hypermethylation of RUNX3 was significantly higher in the neoplastic breast samples (46 of total 61, 75%) including 30 of 40 (75%) DCIS and 16 of 21 (76%) IDC samples (P=0.009). Overall, promoter hypermethylation correlated with RUNX3 inactivation in 42 of 46 (91%) methylated samples (P=0.03). Mislocalized cytoplasmic expression also accounted for RUNX3 inactivation in majority of DCIS (33/40, 83%) and IDC (20/23, 87%) samples independent of promoter hypermethylation. CONCLUSION: Our data suggest that RUNX3 inactivation by promoter hypermethylation and protein mislocalization constitute an early event in breast cancer progression.
Authors: Mohd Feroz Mohd Omar; Kosei Ito; Min En Nga; Ross Soo; Bee Keow Peh; Tuty Muliana Ismail; Bhavin Thakkar; Richie Soong; Yoshiaki Ito; Manuel Salto-Tellez Journal: Pathol Oncol Res Date: 2012-06-24 Impact factor: 3.201
Authors: Erika M Wolff; Gangning Liang; Connie C Cortez; Yvonne C Tsai; J Esteban Castelao; Victoria K Cortessis; Denice D Tsao-Wei; Susan Groshen; Peter A Jones Journal: Cancer Res Date: 2008-08-01 Impact factor: 12.701
Authors: John W Hollingsworth; Shuichiro Maruoka; Kathy Boon; Stavros Garantziotis; Zhuowei Li; John Tomfohr; Nathaniel Bailey; Erin N Potts; Gregory Whitehead; David M Brass; David A Schwartz Journal: J Clin Invest Date: 2008-10 Impact factor: 14.808
Authors: Ilse Van der Auwera; Catherine Bovie; Cecilia Svensson; Xuan B Trinh; Ridha Limame; Peter van Dam; Steven J van Laere; Eric A van Marck; Luc Y Dirix; Peter B Vermeulen Journal: BMC Cancer Date: 2010-03-12 Impact factor: 4.430