p38α signaling induces anoikis and lumen formation during mammary morphogenesis

Huei Chi Wen, Alvaro Avivar-Valderas, Maria Soledad Sosa, Nomeda Girnius, Eduardo F. Farias, Roger J. Davis, Julio A. Aguirre-Ghiso

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

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.

Original languageEnglish (US)
Article numberra34
JournalScience Signaling
Volume4
Issue number174
DOIs
StatePublished - May 24 2011
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint

Dive into the research topics of 'p38α signaling induces anoikis and lumen formation during mammary morphogenesis'. Together they form a unique fingerprint.

Cite this