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THE STEM CELL NICHE

p66Shc/Notch-3 Interplay Controls Self-Renewal and Hypoxia Survival in Human Stem/Progenitor Cells of the Mammary Gland Expanded In Vitro as Mammospheres

^aCenter for Applied Biomedical Research and
Departments of ^dInternal Medicine and Gastroenterology,
^fSurgical and Anesthesiological Sciences, and
^gDepartment of Gastroenterology and Pathology, St. Orsola-Malpighi University Hospital, Bologna, Italy;
Departments of ^bPharmacology,
^cExperimental Pathology, and
^eExperimental Evolutionary Biology, University of Bologna, Italy

Key Words. Stem cells • Self-renewal • Hypoxia • Notch-3 • p66Shc • Carbonic anhydrase IX

Correspondence: Massimiliano Bonafé, M.D., Department of Experimental Pathology, University of Bologna, Bologna, Italy. Telephone: 39-051-636-4009; Fax: 39-051-636-3902; e-mail: massimiliano.bonafe{at}unibo.it

Received July 18, 2006; accepted for publication November 28, 2006.
First published online in STEM CELLS EXPRESS   December 7, 2006.



The comprehension of the basic biology of stem cells is expected to provide a useful insight into the pathogenesis of cancer. In particular, there is evidence that hypoxia promotes stem cell renewal in vitro as well as in vivo. It therefore seems reasonable that stem cell survival and hypoxia response are strictly connected at molecular level. We here report that the 66-kDa isoform of the SHC gene (p66Shc) is induced in a breast cancer cell line by the exposure to hypoxic environment and that it controls the expression of the stem cell regulatory gene Notch-3. Then, we show that p66Shc/Notch-3 interplay modulates self-renewal (by inducing the Notch-ligand Jagged-1) and hypoxia survival (by inducing the hypoxia-survival gene carbonic anhydrase IX) in mammary gland stem/progenitor cells, expanded in vitro as multicellular spheroids (mammospheres). We conclude that mechanisms that regulate stem cell renewal and hypoxia survival are integrated at the level of the p66Shc/Notch3 interplay. Because Notch-3, Jagged-1, and carbonic anhydrase IX are dysregulated in breast cancer, and because p66Shc is an aging-regulating gene, we envision that these data may help in understanding the relationship among aging, cancer, and stem cells.

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