Chemotherapy-Induced Ca2+ Release Stimulates Breast Cancer Stem Cell Enrichment
Authors: Gregg L Semenza
Huimin Zhang
Youngrok Park
Larissa A Shimoda
Haiquan Lu
Linh Tran
Chuanzhao Zhang
Ivan Chen
Journal: Cell Reports (2017)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: breast cancer stem cell; chemotherapy; hypoxia-inducible factors; metastasis; pluripotency factors
Affiliations: Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA., Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA., Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA., Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, and Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: .

Abstract:  Breast cancer stem cells (BCSCs) play a critical role in tumor recurrence and metastasis. Exposure of breast cancer cells to chemotherapy leads to an enrichment of BCSCs. Here, we find that chemotherapy induces the expression of glutathione S-transferase omega 1 (GSTO1), which is dependent on hypoxia-inducible factor 1 (HIF-1) and HIF-2. Knockdown of GSTO1 expression abrogates carboplatin-induced BCSC enrichment, decreases tumor initiation and metastatic capacity, and delays tumor recurrence after chemotherapy. GSTO1 interacts with the ryanodine receptor RYR1 and promotes calcium release from the endoplasmic reticulum. Increased cytosolic calcium levels activate PYK2 → SRC → STAT3 signaling, leading to increased expression of pluripotency factors and BCSC enrichment. HIF inhibition blocks chemotherapy-induced GSTO1 expression and BCSC enrichment. Combining HIF inhibitors with chemotherapy may improve clinical outcome in breast cancer. 

Retracted: No

PubPeer comments:
 Figure 5: More similar than expected. Could the authors check, please? ![file] , 
 Supplemental Fig. S5: More similar than expected ![file] , 
 Dear reader, As the first author of this paper, I sincerely apologize for this error and appreciate for pointing it out. I checked the original data and found that the NANOG blots in Figure 5E and S5E are correct, but copied by mistake to Figure 5D and S5D so they are the same blots. Attached please find the correct raw data for Figure 5D, 5E, S5D and S5E. We will contact with Cell Press for corrigendum. Thank you again for your careful reading and interests in our work. Regards, Haiquan ![file] , 
 CORRECTION: Chemotherapy-Induced Ca2+ Release Stimulates Breast Cancer Stem Cell Enrichment  In the originally published version of this article, the NANOG blot in Figure 5E was inadvertently included in Figure 5D. Likewise, the NANOG blot in Figure S5E was inadvertently included in Figure S5D. The corrected versions of the figures are provided here. Neither the initial errors nor the corrections alter the paperu2019s conclusions. The authors regret the errors. https: www.cell.com cell-reports fulltext S2211-1247(20)31594-1 , 
 In addition to Figure 5i not having a loading control. There appear to be un-natural dots in the protein bands for p-stat3. Can the authors confirm? ![file] , 
 Figure S5E seems to have an un-natural band for KLF4 in lane 3. Can the author check their originals? ![file] , 
 Figure 3A, 5A, 5I, 5J, 6D lack a loading control ![file] ![file] ![file] ![file] , 
 Figure S3A, S5A, S5i,j also lack loading controls. ![file] ![file] ![file] , 
 Figure S5a - p-JAK2 band shows un-natural dots within the pJak2 band. Can the authors check on this? ![file] , 
 Figure 5H, lane 2 of pstat3 contains an unnatural band ![file] , 
 Figure S5d. Stat3 bands and 3rd lane in KLF4 blot look unnatural can the authors check the originals. ![file] , 
 Thank you very much for your interests in our work. As the first author of this paper, I will clarify this concern that these  unnatural bands are because of picture compression. We used Microsoft Powerpoint to organize the figure, and when the raw band pictures were cut and put into powerpoint, they were largely compressed and lost some quality. When we enlarge the single band as big as the comment #5, #6, #9, #10 and #11, we will see some  unnatual dots at the edge of the bands. Haiquan , 
 Got it. Then please post the uncompressed high resolution version of the images. This will be helpful to compare and we can all learn how image compression can make only a few bands appear to have coarse pixels on an otherwise smooth background. ,