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The biochemical mechanisms behind tumor-stromal interactions leading to increased invasiveness and metastasis are mostly unknown. The goal of this study was to analyze the direct effects of staged stroma-derived extracellular matrices on breast cancer cell behavior.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>Early and late three-dimensional matrices were produced by NIH-3T3 and tumor-associated murine fibroblasts, respectively. After removing fibroblasts, extracted matrices were re-cultured with breast epithelial cells of assorted characteristics: MCF-10A (non-tumorigenic), MCF-7 (tumorigenic, non-invasive), and MDA-MB-231 (tumorigenic, invasive). Effects prompted by staged matrices on epithelial cell's growth, morphology and invasion were determined. Also, matrix-induced velocity, directionality and relative track orientation of invasive cells were assessed in the presence or absence of inhibitors of phosphoinositide-3 kinase (PI3K) and\/or beta-1 integrin.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>We observed that assorted breast epithelial cells reacted differently to two-dimensional vs. staged, control (early) and tumor-associated (late), three-dimensional matrices. MCF-10A had a proliferative advantage on two-dimensional substrates while MCF-7 and MDA-MB-231 showed no difference. MCF-10A and MCF-7 formed morphologically distinguishable aggregates within three-dimensional matrices, while MDA-MB-231 exhibited increased spindle-shape morphologies and directional movements within three-dimensional matrices. Furthermore, MDA-MB-231 acquired a pattern of parallel oriented organization within tumor-associated, but not control matrices. Moreover, tumor-associated matrices induced PI3K and beta1-integrin dependent Akt\/PKB activity in MDA-MB-231 cells. Interestingly, beta1-integrin (but not PI3K) regulated tumor-associated matrix-induced mesenchymal invasion which, when inhibited, resulted in a change of invasive strategy rather than impeding invasion altogether.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion<\/jats:title>\n            <jats:p>We propose that both cells and matrices are important to promote effective breast cancer cell invasion through three-dimensional matrices and that beta1-integrin inhibition is not necessarily sufficient to block tumor-matrix induced breast cancer cell invasion. Additionally, we believe that characterizing stroma staging (e.g., early vs. late or tumor-associated) might be beneficial for predicting matrix-induced cancer cell responses in order to facilitate the selection of therapies.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/1471-2407-9-94","type":"journal-article","created":{"date-parts":[[2009,3,26]],"date-time":"2009-03-26T19:14:24Z","timestamp":1238094864000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":95,"title":["Staged stromal extracellular 3D matrices differentially regulate breast cancer cell responses through PI3K and beta1-integrins"],"prefix":"10.1186","volume":"9","author":[{"given":"Remedios","family":"Castell\u00f3-Cros","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David R","family":"Khan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey","family":"Simons","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthildi","family":"Valianou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edna","family":"Cukierman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2009,3,26]]},"reference":[{"issue":"4","key":"1428_CR1","doi-asserted-by":"publisher","first-page":"679","DOI":"10.1016\/j.cell.2006.11.001","volume":"127","author":"GP Gupta","year":"2006","unstructured":"Gupta GP, Massague J: Cancer Metastasis: Building a Framework. 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