p66Shc/Notch-3 interplay controls self renewal and hypoxia survival inhuman stem/progenitor cells of the mammary gland expanded in vitro as mammo-spheres

¹ CRBA, St. Orsola-Malpighi University Hospital, University of Bologna, Bologna, Italy; Department of Pharmacology, University of Bologna, Italy
² CRBA, St. Orsola-Malpighi University Hospital, University of Bologna, Bologna, Italy; Department of Experimental Pathology, University of Bologna, Italy
³ CRBA, St. Orsola-Malpighi University Hospital, University of Bologna, Bologna, Italy; Department of Internal Medicine and Gastroenterology, University of Bologna, Italy
⁴ CRBA, St. Orsola-Malpighi University Hospital, University of Bologna, Bologna, Italy
⁵ CRBA, St. Orsola-Malpighi University Hospital, University of Bologna, Bologna, Italy; Department of Experimental Evolutionary Biology, University of Bologna, Italy
⁶ Department of Surgical and Anesthesiologycal Sciences, S. Orsola-Malpighi University Hospital, Bologna, Italy
⁷ Department of Gastroenterology and Pathology, S. Orsola-Malpighi University Hospital, Bologna, Italy
⁸ CRBA, St. Orsola-Malpighi University Hospital, University of Bologna, Bologna, Italy; Department of Gastroenterology and Pathology, S. Orsola-Malpighi University Hospital, Bologna, Italy

^* To whom correspondence should be addressed. E-mail: massimiliano.bonafe{at}unibo.it.

	Abstract

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 seems therefore reasonable that stem cell survival and hypoxia response are strictly connected at molecular level. We here report that the 66KD isoform of SHC gene (p66Shc) is induced in a breast cancer cell line by the exposure to hypoxic environment, and 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 multi-cellular spheroids (mammospheres). We conclude that mechanisms which regulate stem cell renewal and hypoxia survival are integrated at the level of the p66Shc/Notch3 interplay. Since that Notch-3, Jagged-1 and CA-IX are dys-regulated in breast cancer, and that 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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