Mechanisms Underlying Brain Metastatic Progression in ER+ Breast Cancer
Abstract
Estrogen receptor (ER+) breast cancers (also known as hormone receptor+ or luminal) are the most common subtype of breast cancer. While ER+ breast cancers are effectively treated with anti-estrogen therapies, around one-third of patients will eventually recur long-term, with metastatic ER+ breast cancer most commonly arising in older women with tumors refractory to anti-estrogen therapies. While most effort has been focused on identifying cancer cell mechanisms that drive anti-estrogen resistance, the mechanisms driving outgrowth of ER+ tumors at metastatic sites remain poorly understood. Studies in breast cancer of other subtypes show the communication of cancer cells with the tumor microenvironment (cells at the different metastatic organs) is critical for cancer cells to grow as metastases, yet, how ER+ breast tumors communicate with cells and adapt to grow at metastatic sites and whether blocking these interactions has therapeutic value remains largely unknown. The brain is a particularly understudied site for ER+ breast cancer metastasis as the fraction of ER+ patients developing brain metastasis (BM) is lower compared to HER2-overexpressing (HER2) or triple-negative breast cancer (TNBC). Yet, being the most common subtype of breast cancer, there is a large number of women suffering from ER+ brain metastases. Moreover, the majority of ER+ BCBM arises in women who are older or postmenopausal by virtue of either natural aging or following years of E2-depletion therapies. Yet, the extent to which the E2-depleted or the aged brain modulates the growth of ER+ BMs remains a critical gap that needs to be addressed in order to find effective therapies. FGFR1 amplification was recently reported as the only genomic change associated with an increased risk of late recurrence in post-menopausal women with ER+ early breast cancer on aromatase inhibitor (AI) therapy. Our preliminary data show FGFR1 is highly expressed in our ER+ BC patient-derived xenografts (PDX), and that tumors with high FGFR1 expression showed increased brain colonization in vivo, suggesting FGFR1 signaling may be critical for progression of ER+ BM. Recent studies showed that brain metastases growth (but not arrival or lodging in the brain) cells depends on the ability of metastatic cancer cells to form special communication with specialized cells (astrocytes and neurons) in the brain. Thus, we propose that FGFR1 amplification provides cancer cells with increased ability to interact with these specialized cells and grow as brain metastases. In this proposal, we will investigate how FGFR1 influences brain metastasis outgrowth of ER+ BC in mouse models undergoing anti-estrogen treatments or in the older brain (Aim 1). This could help explain why ER brain metastases tend to arise late in life (older women) or secondary to metastases in other organs. We will also test the window of opportunity for targeting FGFR during progression of ER+ BMs. We will determine if FGFR inhibitors can prevent establishment of ER+ brain metastases, or stop the progression of already-existing brain metastases (Aim 2). This is important, as knowing if a drug is effective early in metastatic progression (i.e., when cells are just beginning to grow in the brain and patients are not likely to know if they have BMs) as compared to late in metastatic progression (i.e., when BMs are clinically detectable) is critical to define what patients will benefit from it. Finally, these studies have high translational potential: We will test FDA-approved FGFR-inhibitors that are currently in phase 1 and 2 clinical trials and appear to have some effect in brain tumors. Thus, if our studies are promising, these drugs could be safely and promptly used in metastatic breast cancer patients. We have developed this proposal in close collaboration with metastatic breast cancer patients and advocates from the Breast Cancer Brain Metastasis Initiative: The Marina Kaplan Project, a subco
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210042
Entities
People
- Diana M Cittelly
Organizations
- United States Army
- University of Colorado Denver