Oncotarget

Research Papers:

Regulation of breast cancer oncogenesis by the cell of origin’s differentiation state

Sarah C. Petrova, Ihsaan Ahmad, Christine Nguyen, Stuart D. Ferrell Jr, Sabrina R. Wilhelm, Yin Ye and Sanford H. Barsky _

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Oncotarget. 2020; 11:3832-3848. https://doi.org/10.18632/oncotarget.27783

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Abstract

Sarah C. Petrova1,*, Ihsaan Ahmad1,*, Christine Nguyen1, Stuart D. Ferrell Jr1, Sabrina R. Wilhelm1, Yin Ye1 and Sanford H. Barsky1

1 Cancer Center and Institute for Personalized Medicine, California University of Science and Medicine, Colton, CA 92324, USA

* These authors contributed equally to this work

Correspondence to:

Sanford H. Barsky,email: BarskyS@cusm.org

Keywords: transgenic mice; induced pluripotent stem cells (iPSCs); breast oncogenesis; differentiation

Received: June 25, 2020     Accepted: September 24, 2020     Published: October 27, 2020

Copyright: © 2020 Petrova et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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.


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