PURPOSE: Neither hormone-related nor genetics risk factors have been associated with the development of highly proliferative HER2-positive breast carcinomas. Because the majority of HER2-positive tumors present the amplification of the oncogene, we asked whether genomic instability triggered by irradiation might be involved in the induction of HER2-overexpressing breast carcinomas. EXPERIMENTAL DESIGN: Sixty-six infiltrating breast carcinomas from patients treated with radiation therapy for Hodgkin's lymphoma or other pediatric solid tumors and a control series of 61 consecutive sporadic breast tumors were analyzed by immunohistochemistry for HER2 expression with HercepTest. A panel of antibodies against estrogen receptor, progesterone receptor, c-kit, cytokeratin 5/6, p53, and ki67 antigen was also used to identify differentiation subsets and molecular characteristics of the analyzed breast carcinomas. RESULTS: Although no differences between the two tumor series were found with respect to HER2 expression scored 2+ and 3+, the percentage of 3+ HER2-positive tumors was significantly higher in patients irradiated during breast maturation compared with patients irradiated after breast maturation (35.3% versus 12.5%, P = 0.046). In the latter group, 52.5% of the breast carcinomas showed basal-like differentiation (estrogen receptor, progesterone receptor, and HER2 negative) versus only 5.9% in the group irradiated during breast development (P < 0.0001). Analysis adjusted for age confirmed the significant increase in basal-like tumor development in patients irradiated within 4 years of menarche, but also showed that the differences between patients irradiated before and after puberty in HER2 3+ tumor frequencies are due to age-related differences in HER2 3+ tumor onset. CONCLUSION: Together, our data indicate that the development of HER2-positive tumors correlates with timing rather than type of carcinogenic hits and provide clear evidence that radiation is a risk factor for breast carcinomas showing basal-like differentiation.
PURPOSE: Neither hormone-related nor genetics risk factors have been associated with the development of highly proliferative HER2-positive breast carcinomas. Because the majority of HER2-positive tumors present the amplification of the oncogene, we asked whether genomic instability triggered by irradiation might be involved in the induction of HER2-overexpressing breast carcinomas. EXPERIMENTAL DESIGN: Sixty-six infiltrating breast carcinomas from patients treated with radiation therapy for Hodgkin's lymphoma or other pediatric solid tumors and a control series of 61 consecutive sporadic breast tumors were analyzed by immunohistochemistry for HER2 expression with HercepTest. A panel of antibodies against estrogen receptor, progesterone receptor, c-kit, cytokeratin 5/6, p53, and ki67 antigen was also used to identify differentiation subsets and molecular characteristics of the analyzed breast carcinomas. RESULTS: Although no differences between the two tumor series were found with respect to HER2 expression scored 2+ and 3+, the percentage of 3+ HER2-positive tumors was significantly higher in patients irradiated during breast maturation compared with patients irradiated after breast maturation (35.3% versus 12.5%, P = 0.046). In the latter group, 52.5% of the breast carcinomas showed basal-like differentiation (estrogen receptor, progesterone receptor, and HER2 negative) versus only 5.9% in the group irradiated during breast development (P < 0.0001). Analysis adjusted for age confirmed the significant increase in basal-like tumor development in patients irradiated within 4 years of menarche, but also showed that the differences between patients irradiated before and after puberty in HER2 3+ tumor frequencies are due to age-related differences in HER2 3+ tumor onset. CONCLUSION: Together, our data indicate that the development of HER2-positive tumors correlates with timing rather than type of carcinogenic hits and provide clear evidence that radiation is a risk factor for breast carcinomas showing basal-like differentiation.
Authors: David H Nguyen; Hellen A Oketch-Rabah; Irineu Illa-Bochaca; Felipe C Geyer; Jorge S Reis-Filho; Jian-Hua Mao; Shraddha A Ravani; Jiri Zavadil; Alexander D Borowsky; D Joseph Jerry; Karen A Dunphy; Jae Hong Seo; Sandra Haslam; Daniel Medina; Mary Helen Barcellos-Hoff Journal: Cancer Cell Date: 2011-05-17 Impact factor: 31.743
Authors: David H Nguyen; Erik Fredlund; Wei Zhao; Charles M Perou; Allan Balmain; Jian-Hua Mao; Mary Helen Barcellos-Hoff Journal: Clin Cancer Res Date: 2013-01-21 Impact factor: 12.531
Authors: Ning Cao; Shiyong Li; Zhaoqing Wang; Kazi Mokim Ahmed; Michael E Degnan; Ming Fan; Joseph R Dynlacht; Jian Jian Li Journal: Radiat Res Date: 2009-01 Impact factor: 2.841
Authors: K E Applegate; W Rühm; A Wojcik; M Bourguignon; A Brenner; K Hamasaki; T Imai; M Imaizumi; T Imaoka; S Kakinuma; T Kamada; N Nishimura; N Okonogi; K Ozasa; C E Rübe; A Sadakane; R Sakata; Y Shimada; K Yoshida; S Bouffler Journal: Radiat Environ Biophys Date: 2020-03-07 Impact factor: 1.925