Document Type

DNP - Open Access

Award Date

2025

Degree Name

Doctor of Philosophy (PhD)

Department / School

Pharmaceutical Sciences

First Advisor

Komal Raina

Abstract

Obesity is a significant risk factor for various cancers, with metabolic dysregulation playing a crucial role in this association. The interplay between obesity-induced metabolic changes and cancer development involves complex biochemical pathways and cellular interactions. Obesity creates a pro-inflammatory microenvironment wherein adipose tissue could interact with cancer-prone cells through hormones, cytokines, and other mediators, increasing cancer risk and progression. Obesity affects metabolic/ lipidomic pathways which are crucial for cancer cell metabolism and growth. These pathways are dysregulated in both cancerous and non-cancerous cells within the tumor microenvironment, linking obesity to cancer development. Dysregulated metabolism, often exacerbated by consumption of modern high-fat and high-fructose diets (literally in every meal) by western societies, could influence cancer progression, particularly in prostate, liver and breast cancers. This dysregulation could affect tumor cells, immune and stromal cells, contributing to tumor growth and immune escape. Obesity is linked to increased risk and progression of breast cancer, particularly estrogen receptor (ER) positive type. This adipocyte and estrogen receptor-positive subtype interaction makes sense, since adipocytes express enzymes such as 17β-hydroxysteroid dehydrogenases (17β-HSDs) and aldo-keto reductases (AKR1C), which are involved in the conversion of estrone, a weaker estrogen, into estradiol, a more potent estrogen. Thus, obesity-associated factors alter metabolic pathways in ER positive-breast cancer cells and the surrounding microenvironment, promoting tumor growth. However, when we remove the hormones (estrogen, progesterone) and other breast cancer driving forces (such as HER2 receptors from the cancer forming and driving equation), it drags us to a logical quandary regarding obesity and its relation with breast cancer; and this is where the heart of this study focused on obesity/aberrant metabolism on triple negative breast cancer (TNBC) lies. As there is a critical gap in our knowledge, it is very essential that we carry out detailed metabolomics/ lipidomics and integrated gene/proteomics studies to understand how obesity/ aberrant metabolism and /or fatty mass close to the breast cancer tissue affects its growth and progression and how non-toxic approaches/ interventions can help reverse these tumorigenic effects. Accordingly, we will, aim I: determine the comparative anti-cancer effects of preventive versus therapeutic regimen of metformin (an anti-obesity/ type II diabetic drug) against TNBC tumorigenesis under different diet-induced obese (DIO) states; aim II: determine the impact of breast/fatty mass-architectural modulation with Asparagus racemosus [root extract (ARRE: a natural galactagogue)] regimen against TNBC tumorigenesis; aim III: use high-tech ‘omics’ technologies to assess the specific proteomic, and/or metabolomic/ lipidomic signatures associated with the treatment responses in study aims I and II. Given our study design and perspective involving DIO models, such as those employing high-fat (HFD) and high-fructose (HFR) diets, metabolic reprogramming intensifies the interplay between lipid alterations and tumor progression. Metabolomics and lipidomics, as demonstrated in this study, provides insight into the functional shifts in major metabolic pathways and lipid classes, revealing significant dysregulations associated with both the cancer state and preventive/ therapeutic interventions. While chapter 1 will review the relevance of metabolomic and lipidomics in cancer; the data outcomes from above defined study aims will be shared in chapters 2 and 3. Briefly, the outcomes from study aim I indicate that Metformin (pre) treatment in both HFD-fed and HFR-fed DIO mice caused an increase in latency time (time taken for appearance of palpable tumors). Also, irrespective of HFD or HFR-fed DIO mice, metformin (pre) treatment had a more enhanced effect on reducing tumor volumes compared to metformin (post) treatment. In metabolomic profiling, the observed metabolic alterations in both the HFD and HFR groups suggest that metformin has the potential to restore metabolic homeostasis in the tumor microenvironment. In lipidomics profiling, the preventive regimen appeared to yield more pronounced lipid alterations, indicating the potential benefits of early metformin intervention in modulating cancer progression. On the other hand, the outcomes of study aim II indicate that ARRE treatment did not have any significant impact on TNBC tumorigenesis; however, it caused an increase in latency time indicating its preventive benefits. Proteomic profiling of mammary gland tissues indicated that 2 molecules (MTHFD1 and MAP4K4) were significantly decreased in the ARRE control (Treated tissue); importantly, these two molecules are reported to be overexpressed in breast cancer and implicated in the growth and progression of breast cancer. Notably, ARRE treatment induces tumor differentiation that could possibly favor the use of ARRE as a preventive or therapeutic modality against anti-TNBC effect-but warrants further investigation.

Library of Congress Subject Headings

Breast -- Cancer -- Etiology.
Breast -- Cancer -- Risk factors.
Obesity.
Metabolism -- Disorders.

Publisher

South Dakota State University

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Available for download on Monday, May 15, 2028

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In Copyright