Item Details

title

ESTROGEN RECEPTOR POSITIVE BREAST CANCER; EVALUATING A METASTATIC MURINE MODEL AND ASSESSING NOVEL THERAPEUTIC COMBINATIONS

author

Langsten, Kendall

abstract

Roughly 75% of patients diagnosed with breast cancer (BC) have estrogen receptor positive (ER+) disease. There is an increased hazard ratio of 5.2 for developing bone metastases with ER+ BC compared with triple-negative (TN) BC and treatments for metastatic ER+ BC are largely palliative. Research advancements have stagnated, in part, due to the lack of animal models of ER+ BC bone metastasis. The purpose of this work was to develop a model of ER+ BC in an immune competent mouse model with spontaneous metastasis and to use that model to gain further understanding of combinatorial treatments. We created a model of ER+ BC using a TN BC cell line transduced to express wild-type human ER. We then injected the ER expressing BC into the mammary fat pad and allowed metastasis to occur. Through this work, we were able to create an ER expressing model of BC that spontaneously metastasized to the bone in immunocompetent mice without exogenous estrogen administration. Next, we assessed the use of an antiestrogen (faslodex), in combination with an anti-CD117 drug (DCC-2618/ripretinib) on ER expressing BC. CD117 is a receptor tyrosine kinase, ligand of stem cell factor, and a cancer stem cell marker that is upregulated by ER signaling. ER expressing BC cells were injected into the mammary fat pad or femur of mice, followed by single or combinatorial antiestrogen and/or anti-CD117 drugs. Histology on the tumors to assess tumor mitoses and necrosis, on the lungs to quantify metastatic burden, and on the hind limbs of both the orthotopic/spontaneous metastasis arm and the direct femoral injection arm was used to assess the drug’s effects. Furthermore, for the direct injections into the femur, we performed bone mineral density analysis using radiography and used μCT to assess bone volume changes. Although each drug exhibited some therapeutic benefit when used singly, when combined that effect was lost. The mechanism for the loss of drug effect is not clear, although this suggests that combined antiestrogen and anti-CD117 therapy may not be therapeutically beneficial for women with ER+ BC. Through this work, we were able to advance what is known about ER expressing BC, and our model holds the potential to gain a deeper understanding of tumor development and metastasis.

subject

antiestrogen treatment

bone metastasis

CD117/c-kit

Estrogen receptor alpha

contributor

Cline, Mark (advisor)

Ornelles, David (committee member)

Caudell, David (committee member)

Cook, Katherine L (committee member)

Miller, Lance (committee member)

date

2024-09-13T08:36:18Z (accessioned)

2024 (issued)

degree

Molecular Medicine and Translational Science (discipline)

embargo

2025-09-12 (terms)

2025-09-12 (liftdate)

identifier

http://hdl.handle.net/10339/109842 (uri)

language

en (iso)

publisher

Wake Forest University

type

Dissertation