Radiation Acts on the Microenvironment to Affect Breast Carcinogenesis by Distinct Mechanisms that Decrease Cancer Latency and Affect Tumor Type

Abstract

SUMMARY 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 TGFβ mediated tumor acceleration; molecular signatures implicated TGFβ and genetically reducing TGFβ abrogated the effect on latency. Surprisingly, tumors from irradiated hosts were predominantly estrogen receptor negative. This effect was TGFβ 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.

Regulation of Mammary Stem Cell Quiescence via Post-Translational Modification of DeltaNp63alpha

“…Other studies have demonstrated increased TGFb signaling in response to UV irradiation [38][39][40]. Additionally, recent studies have implicated TGFb signaling in increased metastasis following ionizing radiation [41] and others have shown that ionizing radiation results in enhanced TGFb signaling from the tumor microenvironment that results in pro-carcinogenic effects [42]. Together these studies indicate that ALK5 signaling mediates DNp63a phosphorylation in response to UV irradiation.…”

“…The observation that UV-initiated phosphorylation of DNp63a was sensitive to A83-01 implicates ALK5 in the cellular response to stress, however, additional studies will be necessary to determine if ALK5-mediated DNp63a phosphorylation contributes to the role of TGFb signaling in promoting metastasis following ionizing radiation [41]. Similarly, it will be of significant interest to determine if the potent TGFb response of the tumor microenvironment to radiation [42] contributes to DNp63a phosphoryla- Figure 6. TGFB treatment destabilizes DNp63a in a manner that is dependent upon the kinase activity of ALK5.…”

Prognosis, stage and oestrogen receptor status of contralateral breast cancer in relation to characteristics of the first tumour, prior endocrine treatment and radiotherapy

“…This is supported by preclinical studies showing radiotherapy to reduce ER-expression in breast cancer cell-lines and rat mammary-tumors (22)(23)(24)(25), as well as to induce ER-negative breast cancer in premenopausal mice (26). Potential explanations could be: Activation of DNA-repair pathways influencing ER-expression (23); Disturbance of ERautoregulation involving micoRNA (27,28); Microenvironmental changes inducing an ERnegative stem-cell-enriched phenotype (29); and promoter-hypermethylation reducing estrogen binding-affinity and signaling (25,28).…”

Microvesicles secreted from human multiple myeloma cells promote angiogenesis

“…It is known that cells communicate and exchange information by employing classical mechanisms, such as secreting soluble factors or cell-to-cell adhesion contacts [32] . Although these classical events have been commonly thought of as the predominant modes of cell-to-cell communication, a novel type of vesicle secretion has recently received a great deal of attention [8,9,15,33] .…”