Hormone Regulation of Tumor Microenvironment in Estrogen Receptor-Positive Breast Cancer by Extracellular Vesicle microRNAs
Abstract
Estrogen receptor positive (ER+) breast cancer (BC) is the most common subtype, representing almost two-thirds of all BCs. There are two overarching challenges that our proposed research project addresses. One is the identification and understanding of the molecular mechanism regulating the development of progressive disease. The second challenge is the detection of ER+ BC patients who have high risk to develop progressive disease and poor prognosis. ER+ BC patients are generally treated with endocrine (hormone) therapy. This therapy aims to block the action of estrogen, which has a pro-tumorigenic effect by stimulating the uncontrolled growth of tumors. Despite the initial responsiveness to the endocrine therapy, a large proportion of patients acquire resistance, which leads to sustained estrogen-mediated tumor cell growth and consequently disease progression and poor prognosis. Because of the large proportion of ER+ BC, the number of deaths is the highest among all BC types. Obesity is a worldwide clinical condition, as more than one-third of the adults are overweight and of these, one-third are obese. Obesity is associated with a higher risk of developing BC, particularly in postmenopausal women, and with worse disease outcome for women of all ages. Importantly, Afro-American women have higher prevalence of obesity and are more likely to be diagnosed at more advanced stages of BC compared with Caucasian women. Furthermore, Afro-American women have a 40% higher BC-related death rate than Caucasian women, and when diagnosed with ER+ BC, they have lower survival rate after 5 years from the diagnosis than Caucasian women. In women, obesity is associated with high levels of estrogen and leptin, due to biosynthesis in the adipose tissue. High levels of both estrogen and leptin play an important role in tumor progression. Therefore, endocrine therapy resistance and obesity determine a sustained hormone-mediated tumor cell growth. Our preliminary studies identified that the stimulation of ER+ BC cells by estrogen induced an increased secretion of microscopic vesicles, called extracellular vesicles (EVs), from ER+ BC cells, which carry high levels of genes called let-7a and let-7d, that are very small regulatory RNA that did not codify for proteins. In addition, it has been found that also leptin can stimulate the secretion of EVs. These let-7 genes have tumor suppressor function inside cancer cells. Therefore, we believe the secretion of let-7 inside the EVs is a strategy by tumor cells to remove and eliminate genes that inhibits tumor cell proliferation. On the other hand, let-7 plays an important role in the regulation of the anti-tumor immune responses by inhibiting the ability of immune cells (such as T lymphocytes) to kill tumor cells. In particular, the secreted EVs carrying let-7 genes can be delivered to immune cells that surround and infiltrate the tumor tissue, be taken up by them, and eventually inhibit their ability to kill tumor cells. We believe that the dual effects of let-7 inside EVs, elimination of tumor suppressor and inhibition of anti-tumor immune responses, play an important role during the progression of the disease. This is particularly important both at early tumor stage, when the microscopic tumor starts to proliferate and disseminate, but also at later tumor stage when, after surgery and during the treatment, tumor cells acquire resistance and give rise to recurrent disease responsible for the poor prognosis. Because estrogen and leptin stimulate the secretion of EVs carrying let-7a and let-7d and adipose tissue of overweight or obese patients produce high level of both estrogen and leptin, we believe that our proposed research project will particularly help ER+ BC patients that are obese or overweight. Furthermore, in our preliminary study, we found that EVs carrying let-7 can be detected in the blood of ER+ BC patients and their levels are higher in the blood of overweight/obese ER+ BC patie
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110031
Entities
People
- Banu Arun
Organizations
- The University of Texas MD Anderson Cancer Center
- United States Army