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: Huei-Chi Wen, Alvaro Avivar-Valderas, Maria Soledad Sosa, Nomeda Girnius, Eduardo F Farias, Roger J Davis, Julio A Aguirre-Ghiso
• Journal: Science signaling (Sci Signal) Vol. 4 Issue 174 Pg. ra34 (May 24 2011) ISSN: 1937-9145 [Electronic] United States
• PMID: 21610252 (Publication Type: Journal Article)

Chemical References

• Activating Transcription Factor 2
• Atf2 protein, mouse
• Mitogen-Activated Protein Kinase 11
• Mitogen-Activated Protein Kinase 14
• MAP Kinase Kinase 3
• MAP Kinase Kinase 6
• Map2k3 protein, mouse
• Map2k6 protein, mouse

Topics

• Activating Transcription Factor 2 (genetics, metabolism)
• Animals
• Anoikis (physiology)
• Cell Line, Tumor
• Female
• MAP Kinase Kinase 3 (genetics, metabolism)
• MAP Kinase Kinase 6 (genetics, metabolism)
• MAP Kinase Signaling System (physiology)
• Mammary Glands, Animal (embryology)
• Mice
• Mice, Knockout
• Mitogen-Activated Protein Kinase 11 (genetics, metabolism)
• Mitogen-Activated Protein Kinase 14 (genetics, metabolism)
• Morphogenesis (physiology)