Date of Award

12-2022

Degree Type

Closed Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology

First Advisor

Ritu Aneja

Second Advisor

Zhi-Ren-Liu

Third Advisor

Keerthi Gogineni

Abstract

Breast cancer (BC) is a heterogeneous disease with diverse clinicopathological characteristics. Triple-negative BC (TNBC) and quadruple-negative BC (QNBC) are aggressive BC subtypes characterized by poor prognosis and therapeutic resistance. TNBC lacks the expression of estrogen and progesterone receptors and amplification of human epidermal growth factor receptor 2. In addition to these receptors, androgen receptor (AR) is absent in QNBC. Molecular and metabolic rewiring may contribute to aggressive phenotypes and treatment resistance in BC. Elucidating the mechanisms underlying tumor aggressiveness and treatment resistance could help identify novel therapeutic targets for BC.

This study provides a two-pronged approach for the management of BC: i) mitigating tumor aggressiveness by targeting novel molecular targets and ii) predicting treatment response based on metabolic profiles. In this study, I evaluated the molecular signatures associated with tumor aggressiveness in TNBC and QNBC. The levels of forkhead box protein M1, kinesin family member C1 (KIFC1), and survivin were positively correlated in TNBC. Upregulation of these molecules enhanced TNBC cell proliferation and migration in vitro and in preclinical animal models, whereas their ablation had the opposite effects. CCAAT/enhancer-binding protein beta (C/EBPβ), a marker linked to tumor aggressiveness, was upregulated in QNBC. C/EBPβ negatively correlated with AR expression and transcriptionally upregulated KIFC1. The C/EBPβ-KIFC1 axis contributed to the high aggressiveness of QNBC.

The second part of the study focused on the determinants of resistance to neoadjuvant chemotherapy (NAC), which is common in patients with BC. Exosomes are small extracellular vesicles that transport their cargo into recipient cells and promote drug resistance. In this study, I found that patients with residual disease (RD) had higher exosome concentrations than those with pathological complete response (pCR). The exosomal metabolic pathways also differed between the two groups.

These findings suggest that i) combination therapy targeting survivin and KIFC1 could serve as a promising treatment alternative for patients with TNBC; ii) inhibition of KIFC1 could help reduce tumor aggressiveness in QNBC; and iii) the relative exosomal levels of succinate and lactate are higher in patients with RD than those with pCR. Collectively, these findings reveal novel strategies for improving targeted therapies for patients with BC.

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