Breast cancers that are resistant to therapy frequently recur years after treatment of the initial disease. Eradication of these recalcitrant cancers depends upon understanding the origins of death-resistance (DR), and the mechanisms underlying tumor dormancy. We have shown a) signaling through the basement membrane (BM) integrins a3/b1 and a6/b4 induces S-1 nonmalignant human HMT-3522 mammary epithelial cells (S-1 MECs) to growth-arrest and form polarized acini, whereas their malignant counterparts (T4-2) fail to growth-arrest or form polar acini in response to these same signals, b) S-1 MECs are dependent on a3/b1-integrin signaling for survival, whereas following malignant transformation (T4-2) they become independent of b1-integrin signaling, c) instead of dying, inhibition of either b1-integrin or epidermal growth factor receptor (EGFR) activity in these T4-2 MECs, induces them to growth-arrest, form polarized acini ('phenotypic reversion', T4-R), and survive in a 'dormant' state, and d) this 'phenotypic reversion' occurs only in the presence of a malleable BM, where these T4-2 MECs receive both the correct biochemical and spatial signals, which allow them to cross-modulate their adhesion and growth factor receptors. We recently found e) that the polarized acini of both S-1 and T4-R MECs are DR to a number of disparate 'apoptosis-inducing' stimuli. As such we have derived the following hypothesis: that given the correct biochemical and spatial cues from the extracellular matrix (ECM), subgroups of tumor cells survive to become dormant and recalcitrant to therapy by exploiting specific integrin-linked pathways. Upon examination we found the BM-induced DR in S-1 and T4-R MEC acini is associated with ligation of a6/b4-integrins and tissue polarity. Thus the objective of these studies is to understand how the BM induces DR in polarized MEC acini via a6/b4-integrins. We will use the HMT-3522 S-1 nonmalignant and T4-2 tumor MEC model, 3D ECM assays and cell and molecular approaches to: 1. Determine how BM signaling through a6/b4-integrins, tissue polarity, acini organization and DR are related. Approaches include testing whether a6/b4-integrins can direct DR in the absence of polarity and a 3D acinar structure, and if not, what degree of polarity or structural organization is necessary. 2. Delineate the minimal signaling events linked to a6/b4-integrin-induced DR by: manipulating a6/b4-integrin-directed hemidesmosome assembly and intracellular signaling through PI3kinase and Shc. 3. Initiate studies to elucidate how DR is induced in MECs through a6/b4-integrins by: examining the relationship between p53 status and a6/b4-integrin induced DR and determining where the apoptotic pathway is blocked. These studies should lead to rational approaches to develop alternate therapies.
| Tharp, Kevin M; Weaver, Valerie M (2018) Modeling Tissue Polarity in Context. J Mol Biol 430:3613-3628 |
| Kaushik, Shelly; Pickup, Michael W; Weaver, Valerie M (2016) From transformation to metastasis: deconstructing the extracellular matrix in breast cancer. Cancer Metastasis Rev 35:655-667 |
| Gilbert, Penney M; Mouw, Janna K; Unger, Meredith A et al. (2010) HOXA9 regulates BRCA1 expression to modulate human breast tumor phenotype. J Clin Invest 120:1535-50 |
| Butcher, Darci T; Alliston, Tamara; Weaver, Valerie M (2009) A tense situation: forcing tumour progression. Nat Rev Cancer 9:108-22 |
| Kumar, Sanjay; Weaver, Valerie M (2009) Mechanics, malignancy, and metastasis: the force journey of a tumor cell. Cancer Metastasis Rev 28:113-27 |
| Levental, Kandice R; Yu, Hongmei; Kass, Laura et al. (2009) Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 139:891-906 |
| Erler, Janine T; Weaver, Valerie M (2009) Three-dimensional context regulation of metastasis. Clin Exp Metastasis 26:35-49 |
| Engler, Adam J; Humbert, Patrick O; Wehrle-Haller, Bernhard et al. (2009) Multiscale modeling of form and function. Science 324:208-12 |
| Rizki, Aylin; Weaver, Valerie M; Lee, Sun-Young et al. (2008) A human breast cell model of preinvasive to invasive transition. Cancer Res 68:1378-87 |
| Fournier, Alaina K; Campbell, Latoya E; Castagnino, Paola et al. (2008) Rac-dependent cyclin D1 gene expression regulated by cadherin- and integrin-mediated adhesion. J Cell Sci 121:226-33 |
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