Microtubules in Breast Cancer: Exploring the α/β-Tubulin Toggle Switch and Its Implications in Human Breast Cancer

Author

• Annemarie Ianos, CUNY Bernard M Baruch CollegeFollow

Date of Award

Spring 5-16-2026

Document Type

Thesis

Degree Name

B.A.

Honors Designation

yes

Program of Study

Chemistry

Language

English

First Advisor

Baofu Qiao

Second Advisor

Keith Ramig

Third Advisor

Pablo Peixoto

Abstract

Microtubules, composed of a/b-tubulin heterodimers, play a central role in breast cancer tumor growth by polymerizing, leading to metastasis and depolymerizing, contributing to proliferation. Human enzymes protein kinase Ca (PKC-a) and cyclin-dependent kinase 1 (Cdk-1) mediate phosphorylation at sites a:Ser165 and b:Ser172, respectively, influencing the growth of microtubules. It is possible that alternating phosphorylation at these sites contribute to an a/b-tubulin “toggle switch” that mediates microtubule instability and tumor growth.

The project investigates the influence of the toggle switch model on microtubule stability by determining the impact of mutants (a:S165D, a:S165N, a:S165S_P, b:S172S_P and a:S165S_P/b:S172S_P) on the hydrolysis of the b-tubulin exchangeable (E-site) guanosine triphosphate (GTP) to guanosine diphosphate (GDP). Atomistic molecular dynamics simulations were used to structurally align GTP, assess hydrogen bonding patterns, and determine interaction energies. It was found that a:S165S_P repels helix 8 (a:Glu254/a:Gln256) by 0.9 Å thereby closing the distance between a:Glu254 and b:GTP by 0.5-0.7 Å. This movement coincides with a shift of the b:GTP nucleotide by 5.0-5.5 Å and stronger longitudinal interactions. In contrast, b:S172S_P phosphorylation displaces the b:T5 loop (b:Asp177) towards b:GTP by 1.1Å while fortifying both lateral and longitudinal interactions. When both sites are phosphorylated, little change is observed. Phosphorylation of a- or b-tubulin generates a distinct profile of secondary structural motions that reposition b:GTP. This research advances the understanding of the toggle switch and the complex molecular factors contributing to microtubule instability leading to breast cancer tumor growth.

Comments

Fourth advisor: Jean Gaffney

Pre-print of manuscript is available on bioRxiv at: https://doi.org/10.64898/2026.04.29.721677 

Recommended Citation

Ianos, Annemarie, "Microtubules in Breast Cancer: Exploring the α/β-Tubulin Toggle Switch and Its Implications in Human Breast Cancer" (2026). CUNY Academic Works.
https://academicworks.cuny.edu/bb_etds/226