Loss of nuclear- cellular- and tissue- architecture is one of the earliest manifestations of malignant progression. In order for a tissue to function properly, tissue architecture must be maintained. We postulated 3 decades ago that there is a reciprocal `signaling integration plan' between the extracellular matrix (ECM) proteins and the nucleus. If this communication remains balanced, tissue homeostasis is maintained. However disruption of any step in reciprocal signaling eventually opens an opportunity for malignant progression. Significant findings include discovery of the indispensible role of laminin-111 (Ln1), a component of the basement membrane (BM). Destruction of Ln1 by unscheduled proteinase activity or dysfunction of surface receptors for Ln1 (such as specific integrins or dystroglycan) and their downstream mediators, disrupts integration plan and leads to inability of breast epithelial cells to correctly polarize and become quiescent thus leading to malignant progression. In previous submission we have defined a number of pathways involved in Ln1/breast cell interactions that mediate integration and, when disrupted, lead to disorganization and malignancy and, if corrected in 3D, revert the malignant phenotype. During last funding cycle we obtained unexpected data that Ln1 signals for quiescence by accelerating the export of actin from the nucleus (N-actin), and if this is prevented, the cells will not enter quiescence. We found Ln1 activates p53 and production of different p53 isoforms. Both the export of N-actin and changes in p53 status provide novel and uncharted pathways linking ECM to changes in the nucleus which lead to altered gene expression that dictate cellular homeostasis vs malignant progression. We have assembled a stellar team of experts to collaborate on these studies. We will use an isogenic breast cancer progression series, primary breast cells from reduction mammoplasty, and cells from genetically engineered mice to investigate how Ln1 in the BM modulates N-actin export and p53 status. We will use techniques such as RNAseq, Mass Spec, ChIPseq, super-resolution microscopy with photobleaching approaches, along with more routine cell, molecular and biochemical techniques such as western blots, IP, IF using additional well-characterized antibodies from our collaborators to investigate changes in gene expression, epigenetic modifications, and changes in p53 isoforms responsible for dramatic alterations in phenotypes as a result of Ln1 signaling. Our proposed work will provide fundamental knowledge about how tissues can remain healthy, as well as providing potential new molecules and pathways that target the microenvironment and the resulting intracellular signaling cascades that can go awry during breast cancer progression.

Public Health Relevance

If we are to treat breast cancers successfully, we must understand how breast architecture is maintained to support normal breast function, and how proper architecture of the breast suppresses malignant progression. We have found that the extracellular matrix protein, laminin-111 (Ln1), is necessary and sufficient for stimulating normal breast tissue architecture and function such as cellular behaviors, gene expression and quiescence. This proposal focuses on understanding the reciprocal communication between Ln1 outside the cell and gene expression by investigating two key nuclear factors: nuclear actin and p53, which serve as essential signaling nodes to achieve normal tissue function.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Tumor Microenvironment Study Section (TME)
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Lawrence Berkeley National Laboratory
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