title: p38α Signaling Induces Anoikis and Lumen Formation During Mammary Morphogenesis.
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.
authors: Department of Medicine, Tisch Cancer Institute at Mount Sinai, Mount Sinai School of Medicine, New York, USA.
authors: Huei-Chi
authors: HC
authors: Wen
authors: Alvaro
authors: A
authors: Avivar-Valderas
authors: Maria Soledad
authors: MS
authors: Sosa
authors: Nomeda
authors: N
authors: Girnius
authors: Eduardo F
authors: EF
authors: Farias
authors: Roger J
authors: RJ
authors: Davis
authors: Julio A
authors: JA
authors: Aguirre-Ghiso
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