ALPHA6/BETA4-INTEGRIN MEDIATED APOPTOSIS RESISTANCE

University Of Pennsylvania, Philadelphia PA

Investigators

Linked publications & trials

Abstract

DESCRIPTION: (Adapted from the investigator's abstract) 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.