Premium
Three‐dimensional Collagen IV and Hormone Prolactin Regulate Breast Cancer Cell Invasion: Role of PAK1 and Matrix Metalloproteinases
Author(s) -
Diakonova Maria,
Oladimeji Peter,
Rider Leah
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.719.1
Subject(s) - pak1 , matrix metalloproteinase , secretion , microbiology and biotechnology , signal transduction , cancer research , prolactin , kinase , matrigel , phosphorylation , biology , chemistry , endocrinology , medicine , hormone , angiogenesis
Three‐dimensional (3D) matrix is a critical component of mammary tissue development not only under physiological but also in pathophysiological conditions. The hormone/cytokine prolactin (PRL) also contributes to the pathogenesis of breast cancer via activation of JAK2/ STAT‐ and MAPK‐dependent pathways. Serine‐threonine kinase PAK1 is one of the targets of PRL‐activated JAK2. We showed previously that tyrosine kinase JAK2 phosphorylates PAK1 in response to PRL on three tyrosines (Tyr 153, 201 and 285). We show herein that the PAK1 phosphorylation is required for maximal PRL‐dependent invasion of human breast cancer cells through Matrigel and that 3D collagen IV acts synergistically with PRL‐activated PAK1 to induce the expression and secretion of MMP‐1 and MMP‐3. In contrast, PRL‐activated PAK1 decreases the 3D collagen IV induction of MMP‐2. MMP‐9 expression and secretion are stimulated by 3D collagen I, not collagen IV, and are not affected by PRL but are down‐regulated by PAK1. Using shRNA or pharmacological inhibitors, we show that MMP‐1 and ‐3 are required and MMP‐2 contributes to PRL‐ dependent invasion. Erk 1/2 signaling appears to be required for the enhanced expression and secretion of MMP‐1, and ‐3 and enhanced PRL‐dependent invasion. p38 MAPK and JNK 1/2 pathways participate in production of MMP‐1 and ‐3 as well as in PRL/PAK1‐dpendent cell invasion. The NFkB pathway is required for MMP‐3 and ‐9 secretion. Together, these data illustrate complex interaction between cellular substrate and PRL regulation of breast cancer cell progression, implicating a pivotal role for PAK1 tyrosyl phosphorylation in MMP regulation. This work was supported by National Institutes of Health Grant R01 DK88127 (to MD).