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SHARPIN regulates collagen architecture and ductal outgrowth in the developing mouse mammary gland
Author(s) -
Peuhu Emilia,
Kaukonen Riina,
Lerche Martina,
Saari Markku,
Guzmán Camilo,
Rantakari Pia,
De Franceschi Nicola,
Wärri Anni,
Georgiadou Maria,
Jacquemet Guillaume,
Mattila Elina,
Virtakoivu Reetta,
Liu Yuming,
Attieh Youmna,
Silva Kathleen A,
Betz Timo,
Sundberg John P,
Salmi Marko,
Deugnier MarieAnge,
Eliceiri Kevin W,
Ivaska Johanna
Publication year - 2016
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201694387
Subject(s) - biology , mammary gland , microbiology and biotechnology , anatomy , breast cancer , genetics , cancer
SHARPIN is a widely expressed multifunctional protein implicated in cancer, inflammation, linear ubiquitination and integrin activity inhibition; however, its contribution to epithelial homeostasis remains poorly understood. Here, we examined the role of SHARPIN in mammary gland development, a process strongly regulated by epithelial–stromal interactions. Mice lacking SHARPIN expression in all cells ( Sharpin cpdm ), and mice with a stromal ( S100a4‐Cre ) deletion of Sharpin, have reduced mammary ductal outgrowth during puberty. In contrast, Sharpin cpdm mammary epithelial cells transplanted in vivo into wild‐type stroma, fully repopulate the mammary gland fat pad, undergo unperturbed ductal outgrowth and terminal differentiation. Thus, SHARPIN is required in mammary gland stroma during development. Accordingly, stroma adjacent to invading mammary ducts of Sharpin cpdm mice displayed reduced collagen arrangement and extracellular matrix ( ECM ) stiffness. Moreover, Sharpin cpdm mammary gland stromal fibroblasts demonstrated defects in collagen fibre assembly, collagen contraction and degradation in vitro . Together, these data imply that SHARPIN regulates the normal invasive mammary gland branching morphogenesis in an epithelial cell extrinsic manner by controlling the organisation of the stromal ECM .