Stromal Modulation of Radiation Carcinogenesis in Breast Cancer
- Author(s): Nguyen, David Hiendat Hua
- Advisor(s): Barcellos-Hoff, Mary Helen
- Buehring, Gertrude
- et al.
Tissue microenvironment is an important determinant of carcinogenesis. We demonstrate that ionizing radiation, a known carcinogen, affects cancer frequency and characteristics by acting on the microenvironment. Using a mammary chimera model in which an irradiated host is transplanted with oncogenic Trp53 null epithelium, we show accelerated development of aggressive tumors whose molecular signatures were distinct from non-irradiated hosts. Molecular and genetic approaches show that TGF-beta mediated tumor acceleration; molecular signatures implicated TGF-beta and genetically reducing TGF-beta abrogated the effect on latency. Surprisingly, tumors from irradiated hosts were predominantly estrogen receptor negative. This effect was TGF-beta independent and linked to mammary stem cell activity. Thus the irradiated microenvironment affects latency and clinically relevant features of cancer through distinct and unexpected mechanisms. Compared to sporadic breast cancer, women treated with radiation for childhood cancers are diagnosed with early onset breast cancer that is more likely to be estrogen receptor negative and have a worse prognosis. Our mammary chimera model shows that host irradiation alone can reduce latency, increase aggressive tumor growth and promote estrogen receptor-negative cancers. Thus changes to the stromal microenvironment rather than DNA damage accounts for many of the features that are observed in radiation-preceded breast cancer. We combined molecular and genetic approaches to identify distinct mechanisms via TGF-beta activity and stem cell deregulation. Our study further shows that host biology significantly alters cancer molecular signatures and such microenvironmental changes are an important biological conduit for cancer risk in humans.