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Sci. Signal., 24 May 2011
Vol. 4, Issue 174, p. ra34
[DOI: 10.1126/scisignal.2001684]


p38α Signaling Induces Anoikis and Lumen Formation During Mammary Morphogenesis

Huei-Chi Wen1,2,3, Alvaro Avivar-Valderas1,2, Maria Soledad Sosa1,2, Nomeda Girnius4, Eduardo F. Farias1, Roger J. Davis4, and Julio A. Aguirre-Ghiso1,2*

1 Department of Medicine, Tisch Cancer Institute at Mount Sinai, Mount Sinai School of Medicine, New York, NY 10029, USA.
2 Department of Otolaryngology, Tisch Cancer Institute at Mount Sinai, Mount Sinai School of Medicine, New York, NY 10029, USA.
3 Department of Biomedical Sciences, School of Public Health, State University of New York at Albany, Rensselaer, NY 12144, USA.
4 Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, MA 01605, USA.

Abstract: The stress-activated protein kinase (SAPK) p38 can induce apoptosis, and its inhibition facilitates mammary tumorigenesis. We found that during mammary acinar morphogenesis in MCF-10A cells grown in three-dimensional culture, detachment of luminal cells from the basement membrane stimulated mitogen-activated protein kinase (MAPK) kinases 3 and 6 (MKK3/6) and p38α signaling to promote anoikis. p38α signaling increased transcription of the death-promoting protein BimEL by phosphorylating the activating transcription factor 2 (ATF-2) and increasing c-Jun protein abundance, leading to cell death by anoikis and acinar lumen formation. Inhibition of p38α or ATF-2 caused luminal filling reminiscent of that observed in ductal carcinoma in situ (DCIS). The mammary glands of MKK3/6 knockout mice (MKK3–/–/MKK6+/– ) showed accelerated branching morphogenesis relative to those of wild-type mice, as well as ductal lumen occlusion due to reduced anoikis. This phenotype was recapitulated by systemic pharmacological inhibition of p38α and β (p38α/β) in wild-type mice. Moreover, the development of DCIS-like lesions showing marked ductal occlusion was accelerated in MMTV-Neu transgenic mice treated with inhibitors of p38α and p38β. We conclude that p38α is crucial for the development of hollow ducts during mammary gland development, a function that may be crucial to its ability to suppress breast cancer.

* To whom correspondence should be addressed. E-mail: julio.aguirre-ghiso{at}

Citation: H.-C. Wen, A. Avivar-Valderas, M. S. Sosa, N. Girnius, E. F. Farias, R. J. Davis, J. A. Aguirre-Ghiso, p38α Signaling Induces Anoikis and Lumen Formation During Mammary Morphogenesis. Sci. Signal. 4, ra34 (2011).

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