Abstract PR14: ErbB2-induced epithelium to mesenchyme transition (EMT) is blocked by p38α/β signaling to restrict early dissemination in breast cancer
Authors: Harper Kathryn , Sosa Maria Soledad , Avivar-Valderas Alvaro , Wen Huei-Chi , Aguirre-Ghiso Julio 
Published: August 2014

Abstract
Our aim is to better understand the mechanisms dictating the early dissemination of cells from pre-malignant lesions, as well as those controlling cell fate decisions at secondary sites to develop more effective therapies for eradicating these populations. The majority of breast cancer patients die from metastatic disease, and not from their primary tumor. The current paradigm argues that dissemination of tumor cells can only occur from invasive lesions observed during late stages of the disease. However, clinical evidence suggests that “pre-malignant” mammary epithelial cells can disseminate and accumulate in target organs like the bone. This can occur from non-invasive lesions such as those found in Ductal Carcinoma in Situ (DCIS) patients. Thus, “early” disseminated tumor cells (DTCs) might be critical contributors to metastasis, but the mechanisms behind these events remain largely unknown. We had shown that p38-alpha/beta signaling maintains mammary gland ductal architecture by promoting anoikis and preventing disorganization of the luminal and basal epithelial compartments. We propose that, in addition to regulating mammary gland morphogenesis, p38-alpha/beta regulates a switch controlling early dissemination. In clinical samples we have found that ErbB2+ DCIS or invasive lesions show a down-regulation of the p38-signaling pathway, suggesting a role for the inhibition of p38-alpha/beta during cancer progression. In MMTV-Neu mammary glands ErbB2 is inversely correlated to membranous beta-catenin (inactive beta-catenin). Further, loss of P-ATF2 (p38 target) also coincides with reduced E-cadherin in this ErbB2+ epithelium. We also reveal that inhibition of p38-alpha/beta in MCF10A-ErbB2 or “pre-malignant” MMTV-ErbB2 acini results in increased invasion and disruption of normal acinar structure. In the MCF10A-ErbB2 model this correlated with E-cadherin down-regulation and induction of an 11-gene Wnt signaling EMT signature (e.g. up-regulation of Wnt5a/b, Wnt11, SNAIL, TWIST, N-cadherin, ZEB2, and SLUG). This EMT signature was also induced simply by p38-alpha/beta inhibition or ErbB2 overexpression in parental MCF10A cells. Further, treatment of MCF10A cells with Wnt3a inhibited p38-alpha and ATF2 phosphorylation. Inhibition of p38-alpha/beta signaling in MMTV-ErbB2 mice strongly increased the accumulation of pre-malignant MECs (detected by surface ErbB2) in the lungs and bone marrow. However, at least in lungs, &gt;80% of these DTCs remained dormant as measure by P-Rb staining. We propose that in pre-malignant lesions p38-alpha/beta acts as an inhibitor to ErbB2-induced EMT, anoikis resistance and early dissemination. We further propose that Wnt signaling executes the EMT and also the silencing of p38-alpha/beta signaling to allow for early dissemination.
This abstract is also presented as Poster B74.
Citation Format: Kathryn Harper, Maria Soledad Sosa, Alvaro Avivar-Valderas, Huei-Chi Wen, Julio Aguirre-Ghiso. ErbB2-induced epithelium to mesenchyme transition (EMT) is blocked by p38α/β signaling to restrict early dissemination in breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr PR14.