Impact of metabolic pathways on ER+ metastatic breast cancer therapy response

Mogol, Ayca Nazli

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https://hdl.handle.net/2142/127469 Copy

Description

Title

Impact of metabolic pathways on ER+ metastatic breast cancer therapy response

Author(s)

Mogol, Ayca Nazli

Issue Date

2024-11-25

Director of Research (if dissertation) or Advisor (if thesis)

Madak Erdogan, Zeynep

Doctoral Committee Chair(s)

Nelson, Erik

Committee Member(s)

• de Mejia, Elvira
• Gaskins, H R

Department of Study

Nutritional Sciences

Discipline

Nutritional Sciences

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

• breast cancer
• metastasis
• endocrine therapy resistance
• fulvestrant
• NAMPT
• ACSS2
• epigenetics

Abstract

Breast cancer is the leading cancer diagnosis among women in the US and the second most common cause of cancer-related death. Although the treatments are effective and successful for the early stages, metastatic breast cancer (MBC) remains a major clinical challenge, with only a 30% 5-year relative survival rate. Additionally, 30-50% of all breast cancer patients bear the risk of recurrence and therapy resistance. Breast cancer is classified into 4 groups based on the presence of hormone receptors (estrogen or progesterone) and human epidermal growth factor receptor 2 (HER2). The most common treatment option for estrogen receptor-positive (ER+) breast cancer patients is endocrine therapies that target estrogen signaling pathways through various mechanisms. Fulvestrant (Fulv), a selective estrogen receptor degrader targeting ER, shows a good response in early-stage patients. However, its efficacy decreases significantly with metastasis, leading to endocrine therapy resistance. For these patients, there is an urgent need for new treatment options. In this study, we investigated metabolic mechanisms behind endocrine therapy resistance and developed alternative strategies to resensitize the MBC cells to Fulv treatment. We first identified molecular changes occurring in MBC cells in response to Fulv, revealing potential vulnerabilities. We identified multiple enzymes whose expression significantly increased with Fulv treatment. Targeting these pathways, we determined the combinations that worked with Fulv to reduce cancer cell viability: nicotinamide phosphoribosyl transferase (NAMPT) inhibitor and acetyl-CoA synthetase (ACSS2) inhibitor combinations with Fulv. The NAMPT inhibitor-Fulv combination proved particularly effective. NAMPT, a rate-limiting enzyme in the NAD recycling pathway, regulates cellular NAD levels. This combination significantly decreased MBC cell viability both in vitro and in vivo while substantially altering gene expression and metabolic profiles. The second combination was ACSS2 inhibitor and Fulv. ACSS2 converts acetate to acetyl-CoA, which is the key substrate for histone acetylation and, thus, has an important role in epigenetic regulation. Fulv treatment increases ACSS2 overexpression, significantly affecting DNA binding patterns of ACSS2 and ERα, as well as chromatin modification (H3K27 acetylation) of critical cell proliferation genes, including CCND1, IGF1R, and FASN. The combination treatment effectively disrupted these Fulv-induced changes and reduced the formation of ACSS2-ER-H3K27ac complexes. In addition to these alternative strategies, we developed potential early detection methods for liver metastasis of breast cancer, which is shown to be more lethal than bone and other visceral tissue metastasis. We showed that survival rates for liver metastatic patients were significantly low compared to other metastatic sites, and when Fulv-treated patients were compared, this difference was more striking. Approximately 7% of Fulv-treated liver metastatic patients were alive, while this number was around 44% for Fulv-treated other metastatic patients. We identified a promising non-invasive detection method combining elevated liver enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST], and alkaline phosphatase [ALP]) with diabetes presence, achieving approximately 80% predictive accuracy for liver metastasis. In conclusion, our findings show that endocrine therapy resistance causes significant alterations in gene expression, metabolic profile, and epigenetic landscape. Targeting some of these alterations offers promising alternative strategies for the treatment of patients with metastatic breast cancer. Furthermore, early diagnosis of metastasis could be used for early intervention, which could increase life expectancy.

Graduation Semester

2024-12

Type of Resource

Thesis

Handle URL

https://hdl.handle.net/2142/127469

Copyright and License Information

Copyright 2024 Ayca Mogol

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