The Hedgehog signaling pathway plays an essential role in maintaining the CD44+CD24-/low subpopulation and the side population of breast cancer cells.
The side population (SP) and the CD44(+)/CD24(-/low) population have been reported in separate studies to include more tumorigenic cells than other populations, and to have the ability to form new tumors and undergo heterogeneous differentiation in breast cancer tissue. However, the relationship between these two populations has not yet been explored in breast cancer cells. Here it is shown that the SP and the CD44(+)/CD24(-/low) populations are overlapping. Both populations were resistant to paclitaxel. Components of the Hedgehog (Hh) signaling pathway were more highly expressed in these cell populations at both the mRNA and protein levels compared with other populations. Furthermore, inhibition of Hh signaling activity suppressed the proliferation of both populations. The significance of Hh signaling activity in the proliferation of both populations was confirmed by the effect of an si-RNA against Gli1, a trans-activator of the Hh signaling pathway, on the proliferation of both populations. These data suggest that the Hh signaling pathway is essential for the proliferation of the tumorigenic population of breast cancer cells, and that this pathway might represent a new candidate for breast cancer therapy targeting cancer stem cells.
Tanaka
Haruo
H
Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan.
Nakamura
Masafumi
M
Kameda
Chizu
C
Kubo
Makoto
M
Sato
Norihiro
N
Kuroki
Syoji
S
Tanaka
Masao
M
Katano
Mitsuo
M
D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000556:secondary; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D051927:CD24 Antigen / Q000378:metabolism*; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000378:metabolism / Q000556:secondary; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D005260:Female; D005434:Flow Cytometry; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D017239:Paclitaxel / Q000627:therapeutic use; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000071676:Zinc Finger Protein GLI1
D000972:Antineoplastic Agents, Phytogenic; D051927:CD24 Antigen; C497889:CD24 protein, human; C497483:CD44 protein, human; C400551:GLI1 protein, human; D053823:Hedgehog Proteins; D018960:Hyaluronan Receptors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D015534:Trans-Activators; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D017239:Paclitaxel