TY - JOUR
T1 - Identification of protein kinase inhibitors to reprogram breast cancer cells
AU - Yuan, Jie
AU - Zhang, Fan
AU - You, Meng
AU - Yang, Qin
N1 - Publisher Copyright:
© 2018, The Author(s).
PY - 2018/9/1
Y1 - 2018/9/1
N2 - Direct reversion of cancers into normal-like tissues is an ideal strategy for cancer treatment. Recent reports have showed that defined transcription factors can induce reprogramming of cancer cells into pluripotent stem cells, supporting this notion. Here, we have developed a reprogramming method that uses a conceptually unique strategy for breast cancer cell treatment. We have screened a kinase inhibitor library and found that Rho-associated protein kinase (ROCK) and mammalian target of rapamycin (mTOR) kinase inhibitors can substitute for all transcription factors to be sufficient to reprogram breast cancer cells into progenitor cells. Furthermore, ROCK–mTOR inhibitors could reprogram breast cancer cells to another terminal lineage-adipogenic cells. Genome-wide transcriptional analysis shows that the induced fat-like cells have a profile different from breast cancer cells and similar to that of normal adipocytes. In vitro and in vivo tumorigenesis assays have shown that induced fat-like cells lose proliferation and tumorigenicity. Moreover, reprogramming treatment with ROCK–mTOR inhibitors prevents breast cancer local recurrence in mice. Currently, ROCK–mTOR inhibitors are already used as antitumor drugs in patients, thus, this reprogramming strategy has significant potential to move rapidly toward clinical trials for breast cancer treatment.
AB - Direct reversion of cancers into normal-like tissues is an ideal strategy for cancer treatment. Recent reports have showed that defined transcription factors can induce reprogramming of cancer cells into pluripotent stem cells, supporting this notion. Here, we have developed a reprogramming method that uses a conceptually unique strategy for breast cancer cell treatment. We have screened a kinase inhibitor library and found that Rho-associated protein kinase (ROCK) and mammalian target of rapamycin (mTOR) kinase inhibitors can substitute for all transcription factors to be sufficient to reprogram breast cancer cells into progenitor cells. Furthermore, ROCK–mTOR inhibitors could reprogram breast cancer cells to another terminal lineage-adipogenic cells. Genome-wide transcriptional analysis shows that the induced fat-like cells have a profile different from breast cancer cells and similar to that of normal adipocytes. In vitro and in vivo tumorigenesis assays have shown that induced fat-like cells lose proliferation and tumorigenicity. Moreover, reprogramming treatment with ROCK–mTOR inhibitors prevents breast cancer local recurrence in mice. Currently, ROCK–mTOR inhibitors are already used as antitumor drugs in patients, thus, this reprogramming strategy has significant potential to move rapidly toward clinical trials for breast cancer treatment.
UR - http://www.scopus.com/inward/record.url?scp=85053240526&partnerID=8YFLogxK
U2 - 10.1038/s41419-018-1002-2
DO - 10.1038/s41419-018-1002-2
M3 - Article
C2 - 30206213
AN - SCOPUS:85053240526
SN - 2041-4889
VL - 9
JO - Cell Death and Disease
JF - Cell Death and Disease
IS - 9
M1 - 915
ER -