title: Dense collagen-I matrices enhance pro-tumorigenic estrogen-prolactin crosstalk in MCF-7 and T47D breast cancer cells.
abstract: Breast cancers that express estrogen receptor alpha (ERα+) constitute the majority of breast tumors. Estrogen is a major driver of their growth, and targeting ER-mediated signals is a largely successful primary therapeutic strategy. Nonetheless, ERα+ tumors also result in the most breast cancer mortalities. Other factors, including altered characteristics of the extracellular matrix such as density and orientation and consequences for estrogen crosstalk with other hormones such as prolactin (PRL), may contribute to these poor outcomes. Here we employed defined three dimensional low density/compliant and high density/stiff collagen-I matrices to investigate the effects on 17β-estradiol (E2) activity and PRL/E2 interactions in two well-characterized ERα+/PRLR+ luminal breast cancer cell lines in vitro. We demonstrate that matrix density modulated E2-induced transcripts, but did not alter the growth response. However, matrix density was a potent determinant of the behavioral outcomes of PRL/E2 crosstalk. High density/stiff matrices enhanced PRL/E2-induced growth mediated by increased activation of Src family kinases and insensitivity to the estrogen antagonist, 4-hydroxytamoxifen. It also permitted these hormones in combination to drive invasion and modify the alignment of collagen fibers. In contrast, low density/compliant matrices allowed modest if any cooperation between E2 and PRL to growth and did not permit hormone-induced invasion or collagen reorientation. Our studies demonstrate the power of matrix density to determine the outcomes of hormone actions and suggest that stiff matrices are potent collaborators of estrogen and PRL in progression of ERα+ breast cancer. Our evidence for bidirectional interactions between these hormones and the extracellular matrix provides novel insights into the regulation of the microenvironment of ERα+ breast cancer and suggests new therapeutic approaches.
authors.affiliation: Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, Wisconsin, United States of America; Cellular and Molecular Biology Program, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Craig E
authors.initials: CE
authors.lastname: Barcus
authors.affiliation: Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Holt
authors.affiliation: Cellular and Molecular Biology Program, University of Wisconsin-Madison, Madison, Wisconsin, United States of America; Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, Wisconsin, United States of America; Laboratory for Cellular and Molecular Biology and Laboratory for Optical and Computational Instrumentation, University of Wisconsin-Madison, Madison, Wisconsin, United States of America; University of Wisconsin Paul P. Carbone Comprehensive Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Keely
authors.affiliation: Cellular and Molecular Biology Program, University of Wisconsin-Madison, Madison, Wisconsin, United States of America; Laboratory for Cellular and Molecular Biology and Laboratory for Optical and Computational Instrumentation, University of Wisconsin-Madison, Madison, Wisconsin, United States of America; University of Wisconsin Paul P. Carbone Comprehensive Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Eliceiri
authors.affiliation: Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, Wisconsin, United States of America; Cellular and Molecular Biology Program, University of Wisconsin-Madison, Madison, Wisconsin, United States of America; University of Wisconsin Paul P. Carbone Comprehensive Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Linda A
authors.initials: LA
authors.lastname: Schuler
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism*; D004958:Estradiol / Q000378:metabolism* / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D011388:Prolactin / Q000378:metabolism* / Q000494:pharmacology; D011981:Receptors, Prolactin / Q000378:metabolism
chemical_list: D024042:Collagen Type I; D047628:Estrogen Receptor alpha; D011981:Receptors, Prolactin; D004958:Estradiol; D011388:Prolactin