title: Regulation of adipose oestrogen output by mechanical stress.
abstract: Adipose stromal cells are the primary source of local oestrogens in adipose tissue, aberrant production of which promotes oestrogen receptor-positive breast cancer. Here we show that extracellular matrix compliance and cell contractility are two opposing determinants for oestrogen output of adipose stromal cells. Using synthetic extracellular matrix and elastomeric micropost arrays with tunable rigidity, we find that increasing matrix compliance induces transcription of aromatase, a rate-limiting enzyme in oestrogen biosynthesis. This mechanical cue is transduced sequentially by discoidin domain receptor 1, c-Jun N-terminal kinase 1, and phosphorylated JunB, which binds to and activates two breast cancer-associated aromatase promoters. In contrast, elevated cell contractility due to actin stress fibre formation dampens aromatase transcription. Mechanically stimulated stromal oestrogen production enhances oestrogen-dependent transcription in oestrogen receptor-positive tumour cells and promotes their growth. This novel mechanotransduction pathway underlies communications between extracellular matrix, stromal hormone output, and cancer cell growth within the same microenvironment.
authors: Department of Molecular Medicine/Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA.
authors: Sagar
authors: S
authors: Ghosh
authors: Keith
authors: K
authors: Ashcraft
authors: Md Jamiul
authors: MJ
authors: Jahid
authors: Craig
authors: C
authors: April
authors: Cyrus M
authors: CM
authors: Ghajar
authors: Jianhua
authors: J
authors: Ruan
authors: Howard
authors: H
authors: Wang
authors: Megan
authors: M
authors: Foster
authors: Daniel C
authors: DC
authors: Hughes
authors: Amelie G
authors: AG
authors: Ramirez
authors: Tim
authors: T
authors: Huang
authors: Jian-Bing
authors: JB
authors: Fan
authors: Yanfen
authors: Y
authors: Hu
authors: Rong
authors: R
authors: Li
mesh_terms: D000273:Adipose Tissue / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D001141:Aromatase / Q000235:genetics / Q000378:metabolism; D001696:Biomechanical Phenomena / Q000187:drug effects; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002417:Cattle; D018929:Cell Culture Techniques; D003094:Collagen / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000494:pharmacology; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D000070819:Discoidin Domain Receptor 1; D004967:Estrogens / Q000096:biosynthesis / Q000378:metabolism*; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D020935:MAP Kinase Signaling System; D040542:Mechanotransduction, Cellular / Q000187:drug effects; D008954:Models, Biological; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D013314:Stress, Mechanical; D017154:Stromal Cells / Q000187:drug effects / Q000201:enzymology; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D017077:Culture Media, Conditioned; D004967:Estrogens; D019012:Integrin beta1; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D003094:Collagen; D001141:Aromatase; C092030:DDR1 protein, human; D000070819:Discoidin Domain Receptor 1; D020794:Receptor Protein-Tyrosine Kinases
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