title: Prolactin signaling through focal adhesion complexes is amplified by stiff extracellular matrices in breast cancer cells.
abstract: Estrogen receptor α positive (ERα+) breast cancer accounts for most breast cancer deaths. Both prolactin (PRL) and extracellular matrix (ECM) stiffness/density have been implicated in metastatic progression of this disease. We previously demonstrated that these factors cooperate to fuel processes involved in cancer progression. Culture of ERα+ breast cancer cells in dense/stiff 3D collagen-I matrices shifts the repertoire of PRL signals, and increases crosstalk between PRL and estrogen to promote proliferation and invasion. However, previous work did not distinguish ECM stiffness and collagen density. In order to dissect the ECM features that control PRL signals, we cultured T47D and MCF-7 cells on polyacrylamide hydrogels of varying elastic moduli (stiffness) with varying collagen-I concentrations (ligand density). Increasing stiffness from physiological to pathological significantly augmented PRL-induced phosphorylation of ERK1/2 and the SFK target, FAK-Y925, with only modest effects on pSTAT5. In contrast, higher collagen-I ligand density lowered PRL-induced pSTAT5 with no effect on pERK1/2 or pFAK-Y925. Disrupting focal adhesion signaling decreased PRL signals and PRL/estrogen-induced proliferation more efficiently in stiff, compared to compliant, extracellular environments. These data indicate that matrix stiffness shifts the balance of PRL signals from physiological (JAK2/STAT5) to pathological (FAK/SFK/ERK1/2) by increasing PRL signals through focal adhesions. Together, our studies suggest that PRL signaling to FAK and SFKs may be useful targets in clinical aggressive ERα+ breast carcinomas.
authors.affiliation: Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI 53706, USA.|Cellular and Molecular Biology Program, University of Wisconsin-Madison, Madison, WI 53706, USA.
authors.forename: Craig E
authors.initials: CE
authors.lastname: Barcus
authors.affiliation: Cellular and Molecular Biology Program, University of Wisconsin-Madison, Madison, WI 53706, USA.|Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, WI 53706, USA.|Laboratory for Cellular and Molecular Biology and Laboratory for Optical and Computational Instrumentation, University of Wisconsin-Madison, Madison, WI 53706, USA.|University of Wisconsin Paul P. Carbone Comprehensive Cancer Center, University of Wisconsin-Madison, Madison, WI 53706, USA.
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Keely
authors.affiliation: Laboratory for Cellular and Molecular Biology and Laboratory for Optical and Computational Instrumentation, University of Wisconsin-Madison, Madison, WI 53706, USA.|University of Wisconsin Paul P. Carbone Comprehensive Cancer Center, University of Wisconsin-Madison, Madison, WI 53706, USA.
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Eliceiri
authors.affiliation: Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI 53706, USA.|Cellular and Molecular Biology Program, University of Wisconsin-Madison, Madison, WI 53706, USA.|University of Wisconsin Paul P. Carbone Comprehensive Cancer Center, University of Wisconsin-Madison, Madison, WI 53706, USA.
authors.forename: Linda A
authors.initials: LA
authors.lastname: Schuler
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D005109:Extracellular Matrix / Q000378:metabolism* / Q000473:pathology; D005260:Female; D022001:Focal Adhesions / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D011388:Prolactin / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D011388:Prolactin
keywords: breast cancer; desmoplasia; extracellular matrix; prolactin; tumor progression