Estrogen-Driven Breast Tumorigenesis in Invasive Lobular Carcinoma
Abstract
The hormone estrogen is well understood to be central to the formation and progression of breast cancer, particularly in tumors containing the estrogen receptor (ER) protein, which is activated by estrogen and drives tumor growth. However, the specific actions of estrogen and ER that cause normal breast cells to become cancerous are poorly understood. This gap in understanding limits our ability to identify which pre-cancerous tumors (for example, in situ carcinomas) will eventually progress to invasive cancer, creating unclear paths for care and leading to patient over-treatment. Based on this, our proposal addresses the Breast Cancer Research Program challenge to identify determinants of breast cancer initiation, risk, or susceptibility, ultimately to conquer the problems of overdiagnosis and overtreatment. A better understanding of estrogen-driven breast cancer progression is especially important for invasive lobular carcinoma (ILC), the most common special histological subtype of breast cancer, which affects ~40,000 U.S. women annually. Nearly all ILC tumors contain ER, and ILC is the breast cancer subtype most strongly linked to estrogen exposure. ILC precursors (atypical lobular hyperplasia, lobular carcinoma in situ) are clinically high risk, associated with a 10-fold increased lifetime risk of developing invasive breast cancer, and are managed aggressively with lifetime active surveillance (including mammograms and/or MRI magnetic resonance imaging) and endocrine therapy-based chemoprevention. However, individual patient risk is poorly understood, and the distinct ILC links to estrogen are not understood. Understanding the cellular processes that underlie estrogen-driven ILC development would dramatically improve our ability to tailor treatment based on risks of cancer progression. Importantly, our work shows ER functions are distinct in ILC cells compared to other breast cancers. We identified an ILC-specific regulator of ER activity (MDC1) that is required for ER function in ILC cells, but the activity of MDC1 during ILC development is unknown. We also identified links between ILC-specific ER functions and loss of the cell-to-cell contact protein E-cadherin, which is the defining molecular feature of ILC. Importantly, E-cadherin loss is an early, key event in ILC initiation and progression, but the impact of E-cadherin loss on estrogen-driven tumor formation has not been explored. We hypothesize E-cadherin loss and ILC-specific activities of MDC1 mediate estrogen-driven lobular cancer formation and progression by reprogramming ER functions in breast cells. To test our hypothesis, we will use human-derived models of cancer initiation and progression from healthy breast cells (and ILC cell lines) and determine how E-cadherin loss and the ILC-specific activity of MDC1 alters ER function and promotes estrogen-driven ILC tumor progression. Our use of human-derived cells is critical because mouse mammary tumors do not contain ER and cannot model clinical estrogen-driven ILC progression, which has hindered prior research. Using human breast cells with ER, we will eliminate E-cadherin, then determine how this alters ER function. Also, we will inject the human breast cells lacking E-cadherin into mouse mammary tissues (to better mimic the breast environment) and examine how E-cadherin loss promotes human breast cells to become ILC. In parallel, we will track how ER and MDC1 cooperate in the genome during progression from pre-cancerous tumors to invasive disease and ultimately metastatic ILC. Through these studies, we will be able to determine how two essential mediators of ILC biology (E-cadherin and MDC1) impact ER activity to promote breast cancer (ILC) initiation and progression from pre-cancerous cells to invasive cancer. Upon completion of this study, we will be able to use identified features of ER remodeling to develop tumor gene expression-based biomarkers that can identify precursors which are likel
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210715
Entities
People
- Matthew J Sikora
Organizations
- United States Army
- University of Colorado Denver