Abstract
Human breast cancer which affects 1/8 women is rare at a cellular level. Even in the setting of germline BRCA1/BRCA2, which is present in all breast cells, solitary cancers or cancers arising at only several foci occur. The overwhelming majority of breast cells (109–1012 cells) resist transformation. Our hypothesis to explain this rareness of transformation is that mammary oncogenesis is regulated by the cell of origin’s critical window of differentiation so that target cells outside of this window cannot transform. Our novel hypothesis differs from both the multi-hit theory of carcinogenesis and the stem/progenitor cell compartmental theory of tumorigenesis and utilizes two well established murine transgenic models of breast oncogenesis, the FVB/N-Tg (MMTV-PyVT)634Mul/J and the FVB-Tg (MMTV-ErbB2) NK1Mul/J. Tail vein fibroblasts from each of these transgenics were used to generate iPSCs. When select clones were injected into cleared mammary fat pads, but not into non-orthotopic sites of background mice, they exhibited mammary ontogenesis and oncogenesis with the expression of their respective transgenes. iPSC clones, when differentiated along different non-mammary lineages in vitro, were also not able to exhibit either mammary ontogenesis or oncogenesis in vivo. Therefore, in vitro and in vivo regulation of differentiation is an important determinant of breast cancer oncogenesis.
Highlights
Cancers are common diseases in people and yet, on a cellular level, are quite rare [1,2,3]
Tail vein fibroblasts could successfully be obtained from both female transgenics, the FVB/N-Tg (MMTVPyVT)634Mul/J and the FVB-Tg (MMTV-ErbB2) NK1Mul/J and control noncarrier FVB mice
The tail vein fibroblasts were transfected with a cocktail of stem cell-inducing reporter genes, which were generated through a retroviral packaging cell line
Summary
Cancers are common diseases in people and yet, on a cellular level, are quite rare [1,2,3]. Attempts to explain the rareness of breast cancer at a cellular level have invoked the multi-hit theory of carcinogenesis, which basically opines that breast cancers do not occur unless there has been an accumulation of all of the necessary hits within the cell of origin [10, 11]. The multi-hit theory falls short in explaining the rareness of transformation at a cellular level [12,13,14,15,16,17] This is so because the germline inherited BRCA1/BRCA2 breast cancers are caused by only 1 or 2 hits and certainly not multiple hits. Hormone replacement therapy, dietary carcinogens and pesticide www.oncotarget.com exposure which cause the multi-hit spontaneous, sporadic breast cancers would be expected to bathe all the cells of the breast, subjecting them to all the “hits” required for carcinogenesis
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