Beschreibung:
<jats:title>Abstract</jats:title>
<jats:p>Breast cancer (BC) is clinically classified according to expression of estrogen receptor, progesterone receptor (ER+ BC), HER2 (HER2+), or absence of these markers (triple negative BC). While TNBC has the inferior prognosis in the short term, ER+ breast cancer has an extended risk of recurrence that lasts up to 20 years and accounts for the most deaths overall. Cytokeratin 5 (CK5) is an intermediate filament protein that is expressed in the majority of TNBC cases and 10-50% of ER+ BC. In CK5+/ER+ BC, there is widespread heterogeneity in the amount of CK5+ tumor cells (~1-50%). The mere presence of CK5+ cells is an indicator of poor prognosis across both subtypes of BC; the reasons for this are poorly understood. We have shown that CK5+ cells within ER+ and TNBC cell lines, and heterogeneous PDX tumor models lose membrane localization of adherens junction proteins β-catenin and E-cadherin. Loss of membrane β-catenin and E-cadherin is associated with poor prognosis in breast cancer and is a precursor to cell invasion. CK5+ cells have been reported to have increased invasive potential by us and others. Thus, identifying the mechanism of CK5-dependent loss of adherens proteins at the membrane could lead to development of therapies targeting this process. β-catenin and E-cadherin localization have been reported to be regulated through endocytosis which is mediated through the small GTPase family of Rab proteins. We performed a screen to identify potential CK5 interacting proteins in breast cancer cells and identified several Rab proteins. Thus, we hypothesize that CK5 acts as a scaffold for Rabs to promote endocytosis of β-catenin and E-cadherin to increase invasive potential.To investigate this, we treated CK5 overexpressing ER+ and TNBC cells with the endocytosis inhibitor Dyngo4a and found membrane β-catenin and E-cadherin localization were restored, suggesting that CK5 may be mediating endocytosis of β-catenin and E-cadherin. Rab5 is responsible for trafficking vesicles from the plasma membrane to the early endosomes. CK5 was confirmed to interact with Rab5 by co-IP in TNBC and CK5 overexpressing ER+ cell lines. In ongoing studies, we are testing whether Rab5 knockdown prevents loss of membrane β-catenin and E-cadherin and decreases cell invasiveness. These experiments will collectively determine whether CK5 regulated endocytosis is a targetable feature in breast cancer cells.</jats:p>
<jats:p>Citation Format: Olivia Frances McGinn, Ashley V. Ward, Jessica Finlay-Schultz, Kiran Vinod Paul, Peter Kabos, Carol Sartorius. Cytokeratin 5 promotes endocytosis to remodel cell adhesions in breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2605.</jats:p>