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Molecular regulators of apical/basal polarity during mammary epithelial morphogenesis and invasive tumor progression Somasiri, Aruna Mahendra

Abstract

During breast cancer progression, the mammary gland undergoes architectural changes marked by a disruption of epithelial apical/basal polarity. In infiltrating lobular carcinomas (ILC) this disruption is marked by a loss of adherens (AJ) and tight (TJ) junctions. However, in the more prevalent infiltrating ductal carcinomas (IDC), AJ often remain while TJ are lost or disorganized. Thus, the loss of TJ polarity may be an important component of invasive, cancer progression. Because TJs and the basement membrane (BM) are critical components of apical and basal polarity, I chose to study the importance of polarity changes during breast cancer progression. To identify the molecular regulators of TJ dynamics in the normal breast I used a 3D hierarchical model of mammary epithelial cell morphogenesis in vitro. In this hierarchy, functional AJ were initially formed and then the TJs were formed. These TJs were not polarized and the TJ scaffolding protein ZO-1 co-localized with the AJ protein β-catenin at AJs. Upon addition of a soluble BM, ZO-1 was released from the AJ complex and the TJ complex migrated apically. This apical polarization of the TJ was mediated, at least in part, by interactions of the α6β4 integrin with laminin in the BM. The ETV6-NTRK3 (EN) fusion protein is expressed in secretory breast carcinomas (SBC) and two proteins, Podocalyxin and the Integrin-linked kinase (ILK), are involved in modulating cell-cell junctions. Thus, I examined the effects of these three genes on cell polarity. Forced expression of EN in normal epithelial cells induced cell proliferation without affecting TJ polarity, further explaining the non-metastatic phenotype of SBC. Podocalyxin was highly expressed in a subset of ductal tumors that become metastatic. When podocalyxin was expressed in a well-differentiated breast cancer cell line, TJs and polarity were perturbed, resulting a phenotype similar to IDC. When ILK was expressed in normal epithelial cells, they completely lost both TJs and AJs initiating an epithelial to mesenchymal transformation, hence an ILC phenotype. These data suggest that the establishment of polarized TJs is critical for normal mammary epithelial architecture, while changes to this architecture, at least in part, contribute to invasive breast tumor progression.

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