Mitosis, Cytoskeleton Regulation, and Drug Resistance in Receptor Triple Negative Breast Cancer

TL;DR

This study investigates the unique microtubule dynamics and spindle behaviors in aggressive triple-negative breast cancer cells, identifying potential therapeutic targets by analyzing spindle mechanics and proposing optimal tubulin inhibitors.

Contribution

It reveals abnormal spindle oscillations and rapid microtubule polymerization in TNBC cells, suggesting disrupted spindle positioning as a therapeutic target and proposing a strategy for selecting tubulin inhibitors.

Findings

MDA-MB-231 cells show largest spindles and rapid spindle twisting.

High microtubule polymerization rates are linked to tumor aggressiveness.

Proposed strategy for selecting tubulin inhibitors based on microtubule dynamics.

Abstract

During cell division, the receptor triple-negative MDA-MB-231 mitotic spindles are the largest in comparison to other BC cell lines. Many of the MDA-MB-231 spindles exhibit rapid lateral twisting during metaphase, which remains unaffected by knockdown of the oncogene Myc and treatment with inhibitors of the serine/threonine-protein kinase B-Raf and the epidermal growth factor receptor (EGFR), alone or in any combination. The MDA-MB-231 cells are the most aggressive and rapidly form metastatic tumors in xenograft transplant models, and exhibited very high proliferation rates when plated as three-dimensional cultures in Matrigel. Quantitative image analysis of microtubules (MTs) in six BC cell lines - MDA-MB-231 (receptor negative), HCC-1143 (receptor negative), HCC-3153 (receptor negative), ZR75B (estrogen receptor-positive), LY2 (progesterone receptor-positive), HCC-1428 (estrogen receptor-positive, progesterone receptor-positive) - demonstrated that the rotational spindle rocking of MDA-MB-231 cells during metaphase appears coupled with a significant increase in MT polymerization rates during interphase, which likely shortens interphase and accelerates cell cycle progression and mitotic entry. Unlike the uniform treadmilling rates of about 21 um/min in kinetochore MTs during metaphase we measured across cell lines, MDA-MB-231 cells in interphase exhibit the fastest MT polymerization dynamics of about 19 um/min and this is coupled with abnormal mitotic spindle oscillations of almost 30 um/min. This aberrant behavior in MDA-MB-231 spindles may represent a therapeutically targetable disrupted mechanism of spindle positioning in receptor triple-negative breast cancer (TNBC) cells leading to tumor aggressiveness. In this manuscript, we outline a strategy for the selection of the most optimal tubulin inhibitor based on the ability to affect MT dynamics.