PLEKHA7, an Apical Adherens Junction Protein, Suppresses Inflammatory Breast Cancer in the Context of High E-Cadherin and p120-Catenin Expression

Abstract

Inflammatory breast cancer is a highly aggressive form of breast cancer that forms clusters of tumor emboli in dermal lymphatics and readily metastasizes. These cancers express high levels of E-cadherin, the major mediator of adherens junctions, which enhances formation of tumor emboli. Previous studies suggest that E-cadherin promotes cancer when the balance between apical and basolateral cadherin complexes is disrupted. Here, we used immunohistochemistry of inflammatory breast cancer patient samples and analysis of cell lines to determine the expression of PLEKHA7, an apical adherens junction protein. We used viral transduction to re-express PLEKHA7 in inflammatory breast cancer cells and examined their aggressiveness in 2D and 3D cultures and in vivo. We determined that PLEKHA7 was deregulated in inflammatory breast cancer, demonstrating improper localization or lost expression in most patient samples and very low expression in cell lines. Re-expressing PLEKHA7 suppressed proliferation, anchorage independent growth, spheroid viability, and tumor growth in vivo. The data indicate that PLEKHA7 is frequently deregulated and acts to suppress inflammatory breast cancer. The data also promote the need for future inquiry into the imbalance between apical and basolateral cadherin complexes as driving forces in inflammatory breast cancer.

Origin and Evolution of the Multifaceted Adherens Junction Component Plekha7

“…PLEKHA7 was originally identified as an E-cadherin–p120 binding partner, specific to the apical AJs in mature epithelial tissues and monolayers, tethering the minus ends of the microtubules to the AJs ( Meng et al, 2008 ; Pulimeno et al, 2010 ; Pulimeno et al, 2011 ). Since then, multiple additional roles have been attributed to PLEKHA7, including cell-cell junction stabilization through interactions with junctional and cytoskeletal components ( Kurita et al, 2013 ; Paschoud et al, 2014 ; Guerrera et al, 2016 ; Kourtidis and Anastasiadis, 2016 ; Lee et al, 2017 ); recruitment and regulation of the RNA interference (RNAi) machinery at AJs ( Kourtidis et al, 2015 ; Kourtidis et al, 2017b ; Nair-Menon et al, 2020 ); regulation of hypertension ( Endres et al, 2014 ); function as a tumor suppressor ( Kourtidis et al, 2015 ; Tille et al, 2015 ; Rea et al, 2018 ; Nair-Menon et al, 2020 ; Pence et al, 2021 ); regulation of responses to bacterial toxins ( Popov et al, 2015 ; Shah et al, 2018 ), and involvement in neocortex development ( Tavano et al, 2018 ). Although these studies exemplify the importance of PLEKHA7 in human health and disease, little is known regarding the roles of PLEKHA7 in non-mammalian species.…”

From the Matrix to the Nucleus and Back: Mechanobiology in the Light of Health, Pathologies, and Regeneration of Oral Periodontal Tissues

“…The main constituents of the so-called adherens junctions (AJs) are cadherin (Cad)-family members (Cads), which are Ca 2+ -dependent, membrane-embedded proteins that connect cells via homophilic interaction [93]. In the cytoplasm, Cads are connected to various proteins, amongst others α-catenin, p120, vinculin or β-catenin [22,[94][95][96]. These adaptor proteins are comparable to the integrin-linked intracellular mechanotransducers, as they connect Cads to the actin cytoskeleton.…”

“…The histological equivalents of these connections are called adherens junctions (AJs) and are indispensable for epithelial integrity and barrier functions. Similar to FAs, AJs are intracellularly coupled to further signal-transducing proteins comprising members of the catenin family and the actin cytoskeleton [22][23][24].…”

Bioengineered PLEKHA7 nanodelivery regularly induces behavior alteration and growth retardation of acute myeloid leukemia

“…PLEKHA7 plays a fundamental role in epithelial integrity whereby they combine to associate with actin filaments in the cytoskeleton [ 9 , 10 ]. Consequently, several studies have discussed the dual oncogenic and tumor suppression activities of PLEKHA7 according to cancer type, such as breast cancer [ 11 , 12 ].…”