Brett Fleisher1, Carolin Werkman1, Brehanna Jacobs1, Justin Varkey1, Kareem Taha1, Sihem Ait-Oudhia2. 1. Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, University of Florida, College of Pharmacy, Orlando, FL, U.S.A. 2. Quantitative Pharmacology and Pharmacometrics (QP2), Merck & Co., Inc, Kenilworth, NJ, U.S.A.
Abstract
BACKGROUND/AIM: Triple-negative breast cancer (TNBC) prevalence and risk of relapse are greatest in African American (AA) patients. Doxorubicin (DOX) and abemaciclib (ABE) synergism in Rb-positive TNBC cells (MDA-MB-231), and antagonism in Rb-negative TNBC cells (MDA-MB-468) have been previously shown. Here, we assessed Kinesin-like protein 1 (KIFC1) as an ethnic-specific prognostic biomarker of the DOX+ABE combination for the Rb-status in TNBC. MATERIALS AND METHODS: Literature search for TNBC prognostic biomarkers in the AA population was conducted. MDA-MB-231 and MDA-MB-468 cells were exposed over 72 h to four treatment arms: 1) control (medium without drug), 2) DOX at 50% inhibitory concentration in MDA-MB-231 (0.565 μM) and MDA-MB-468 (0.121 μM), 3) ABE alone (2 μM), and 4) DOX+ABE combination at their corresponding concentrations in each cell-line. KIFC1 protein expression and temporal changes were quantified in MDA-MB-231 cells using western blot. RESULTS: KIFC1, Kaiso, and Annexin A2 are literature-identified AA-specific TNBC prognostic biomarkers. KIFC1 was found to be uncorrelated to other proposed biomarkers, suggesting it may predict risk independently of other TNBC biomarkers. In both cell lines, DOX alone did not significantly change KIFC1 expression relative to control. Conversely, ABE reduced KIFC1 expression in MDA-MB-231 but not in MDA-MB-468 cells. The combination DOX+ABE resulted in a greatest reduction in KIFC1 in MDA-MB-231 cells with a more rapid time-to-full inhibition of KIFC1 compared to ABE alone. CONCLUSION: Change in KIFC1 expression is primarily driven by ABE in Rb-positive TNBC cells. DOX increases ABE speed to achieve a full inhibition of KIFC1 in Rb-positive, yet, without influencing its expression in Rb-negative TNBC cells. Copyright 2022, International Institute of Anticancer Research.
BACKGROUND/AIM: Triple-negative breast cancer (TNBC) prevalence and risk of relapse are greatest in African American (AA) patients. Doxorubicin (DOX) and abemaciclib (ABE) synergism in Rb-positive TNBC cells (MDA-MB-231), and antagonism in Rb-negative TNBC cells (MDA-MB-468) have been previously shown. Here, we assessed Kinesin-like protein 1 (KIFC1) as an ethnic-specific prognostic biomarker of the DOX+ABE combination for the Rb-status in TNBC. MATERIALS AND METHODS: Literature search for TNBC prognostic biomarkers in the AA population was conducted. MDA-MB-231 and MDA-MB-468 cells were exposed over 72 h to four treatment arms: 1) control (medium without drug), 2) DOX at 50% inhibitory concentration in MDA-MB-231 (0.565 μM) and MDA-MB-468 (0.121 μM), 3) ABE alone (2 μM), and 4) DOX+ABE combination at their corresponding concentrations in each cell-line. KIFC1 protein expression and temporal changes were quantified in MDA-MB-231 cells using western blot. RESULTS: KIFC1, Kaiso, and Annexin A2 are literature-identified AA-specific TNBC prognostic biomarkers. KIFC1 was found to be uncorrelated to other proposed biomarkers, suggesting it may predict risk independently of other TNBC biomarkers. In both cell lines, DOX alone did not significantly change KIFC1 expression relative to control. Conversely, ABE reduced KIFC1 expression in MDA-MB-231 but not in MDA-MB-468 cells. The combination DOX+ABE resulted in a greatest reduction in KIFC1 in MDA-MB-231 cells with a more rapid time-to-full inhibition of KIFC1 compared to ABE alone. CONCLUSION: Change in KIFC1 expression is primarily driven by ABE in Rb-positive TNBC cells. DOX increases ABE speed to achieve a full inhibition of KIFC1 in Rb-positive, yet, without influencing its expression in Rb-negative TNBC cells. Copyright 2022, International Institute of Anticancer Research.
Authors: Helena Grinberg-Rashi; Efrat Ofek; Marina Perelman; Jozef Skarda; Pnina Yaron; Marián Hajdúch; Jasmin Jacob-Hirsch; Ninette Amariglio; Meir Krupsky; David A Simansky; Zvi Ram; Raphael Pfeffer; Ilana Galernter; David M Steinberg; Issachar Ben-Dov; Gideon Rechavi; Shai Izraeli Journal: Clin Cancer Res Date: 2009-02-03 Impact factor: 12.531
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