Differential contextual responses of normal human breast epithelium to Ionizing radiation in a mouse xenograft model. / Coates, Philip J.; Appleyard, M. Virginia C. L.; Murray, Karen; Ackland, Caroline; Gardner, June; Brown, Douglas C.; Adamson, Dougal J. A.; Jordan, Lee B.; Purdie, Colin A.; Munro, Alastair J.; Wright, Eric G.; Dewar, John A.; Thompson, Alastair M.
In: Cancer Research, Vol. 70, No. 23, 01.12.2010, p. 9808-9815.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Differential contextual responses of normal human breast epithelium to Ionizing radiation in a mouse xenograft model
A1 - Coates,Philip J.
A1 - Appleyard,M. Virginia C. L.
A1 - Murray,Karen
A1 - Ackland,Caroline
A1 - Gardner,June
A1 - Brown,Douglas C.
A1 - Adamson,Dougal J. A.
A1 - Jordan,Lee B.
A1 - Purdie,Colin A.
A1 - Munro,Alastair J.
A1 - Wright,Eric G.
A1 - Dewar,John A.
A1 - Thompson,Alastair M.
AU - Coates,Philip J.
AU - Appleyard,M. Virginia C. L.
AU - Murray,Karen
AU - Ackland,Caroline
AU - Gardner,June
AU - Brown,Douglas C.
AU - Adamson,Dougal J. A.
AU - Jordan,Lee B.
AU - Purdie,Colin A.
AU - Munro,Alastair J.
AU - Wright,Eric G.
AU - Dewar,John A.
AU - Thompson,Alastair M.
PY - 2010/12/1
Y1 - 2010/12/1
N2 - <p>Radiotherapy is a key treatment option for breast cancer, yet the molecular responses of normal human breast epithelial cells to ionizing radiation are unclear. A murine subcutaneous xenograft model was developed in which nonneoplastic human breast tissue was maintained with the preservation of normal tissue architecture, allowing us to study for the first time the radiation response of normal human breast tissue in situ. Ionizing radiation induced dose-dependent p53 stabilization and p53 phosphorylation, together with the induction of p21(CDKN1A) and apoptosis of normal breast epithelium. Although p53 was stabilized in both luminal and basal cells, induction of Ser392-phosphorylated p53 and p21 was higher in basal cells and varied along the length of the ductal system. Basal breast epithelial cells expressed Delta Np63, which was unchanged on irradiation. Although stromal responses themselves were minimal, the response of normal breast epithelium to ionizing radiation differed according to the stromal setting. We also demonstrated a dose-dependent induction of gamma-H2AX foci in epithelial cells that was similarly dependent on the stromal environment and differed between basal and luminal epithelial cells. The intrinsic differences between human mammary cell types in response to in vivo irradiation are consistent with clinical observation that therapeutic ionizing radiation is associated with the development of basal-type breast carcinomas. Furthermore, there may be clinically important stromal-epithelial interactions that influence DNA damage responses in the normal breast. These findings demonstrate highly complex responses of normal human breast epithelium following ionizing radiation exposure and emphasize the importance of studying whole-tissue effects rather than single-cell systems. Cancer Res; 70( 23); 9808-15. (C)2010 AACR.</p>
AB - <p>Radiotherapy is a key treatment option for breast cancer, yet the molecular responses of normal human breast epithelial cells to ionizing radiation are unclear. A murine subcutaneous xenograft model was developed in which nonneoplastic human breast tissue was maintained with the preservation of normal tissue architecture, allowing us to study for the first time the radiation response of normal human breast tissue in situ. Ionizing radiation induced dose-dependent p53 stabilization and p53 phosphorylation, together with the induction of p21(CDKN1A) and apoptosis of normal breast epithelium. Although p53 was stabilized in both luminal and basal cells, induction of Ser392-phosphorylated p53 and p21 was higher in basal cells and varied along the length of the ductal system. Basal breast epithelial cells expressed Delta Np63, which was unchanged on irradiation. Although stromal responses themselves were minimal, the response of normal breast epithelium to ionizing radiation differed according to the stromal setting. We also demonstrated a dose-dependent induction of gamma-H2AX foci in epithelial cells that was similarly dependent on the stromal environment and differed between basal and luminal epithelial cells. The intrinsic differences between human mammary cell types in response to in vivo irradiation are consistent with clinical observation that therapeutic ionizing radiation is associated with the development of basal-type breast carcinomas. Furthermore, there may be clinically important stromal-epithelial interactions that influence DNA damage responses in the normal breast. These findings demonstrate highly complex responses of normal human breast epithelium following ionizing radiation exposure and emphasize the importance of studying whole-tissue effects rather than single-cell systems. Cancer Res; 70( 23); 9808-15. (C)2010 AACR.</p>
KW - TARGETED INTRAOPERATIVE RADIOTHERAPY
KW - MAMMARY-GLAND DEVELOPMENT
KW - NORMAL-TISSUE-REACTIONS
KW - ATHYMIC NUDE-MICE
KW - IN-VIVO
KW - CANCER RISK
KW - ATAXIA-TELANGIECTASIA
KW - GAMMA-IRRADIATION
KW - P53 EXPRESSION
KW - INDUCTION
U2 - 10.1158/0008-5472.CAN-10-1118
DO - 10.1158/0008-5472.CAN-10-1118
M1 - Article
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 23
VL - 70
SP - 9808
EP - 9815
ER -