Washington, DC – A protein known to be overly active in breast cancer can exist in a form that seems to change the structural composition of mammary tissue, potentially making it more conducive to tumor progression, say researchers from the Lombardi Comprehensive Cancer Center at Georgetown University Medical Center (GUMC).
At the annual meeting of the Endocrine Society in Washington, DC, the scientists report that the protein, AIB1 (Amplified in Breast Cancer 1), has a shorter form known as AIB1delta3 which turns breast tissue more fibrous. The researchers say this shorter form may contribute to the dense breast tissue that is a known risk factor for breast cancer.
"We found that AIB1delta3 alters the stroma, or environment that surrounds and supports cancer cells, producing excessive fibrosis," says the study's lead author, Priscilla Furth, MD, Professor of Oncology and Medicine. "This is significant, because disordered interactions between the epithelial and stromal compartments are being increasingly recognized as an important component of breast cancer risk."
A splice variant occurs as the gene is expressed, resulting in deletion of extra amino acids when the protein is formed, changing its shape and possibly its function. Many genes produce these kinds of variants, and the GUMC researchers wanted to know if AIB1delta3 played the same role, or a different one, than its parent larger protein, AIB1, which is known to be over-produced at the RNA level in a significant portion of breast cancers.
Previous research at GUMC has found that AIB1 acts as a co-activator of growth proteins, such as estrogen receptor alpha and HER2/neu, which are also often over-expressed in tumor development. "AIB1 and its more active variant potentiate both estrogen and HER2/Neu at different stages of breast cancer. We knew that AIB1 delta 3 was more active than AIB1 but this study is evidence that we have of a major functional difference between the two proteins," says the study's other senior author, Anna Riegel, PhD, a professor of oncology and associate director for cancer research education at Lombardi.
In this study, the researchers used transgenic mice in which either the AIB1 or the AIB1delta3 slice variant gene were over-expressed. Upon examination of mammary tissue, they found that the tissue in mice with the splice variant of AIB1 was thicker than that seen in mice with too much of the parent protein. This fibrosis may be related to the hard, scar-like tissue frequently seen around a breast tumor, Furth says. "What we don't know is whether generation of this dense tissue, which seems to increase growth factor responses, is required for cancer to develop, or whether cancer would regress if development of this abnormal stroma was interrupted," she says.
Investigators in the project include Maddalena Tilli, degreenow an Assistant Professor in the department of Biology at Georgetown University, and Rebecca Nakles, a graduate student in the Tumor Biology Training Program at Georgetown University.
The National Cancer Foundation, National Institutes of Health and the Susan G. Komen Foundation funded the study.
Riegel and Furth report no related financial interests.
About Lombardi Comprehensive Cancer Center
The Lombardi Comprehensive Cancer Center, part of Georgetown University Medical Center and Georgetown University Hospital, seeks to improve the diagnosis, treatment, and prevention of cancer through innovative basic and clinical research, patient care, community education and outreach, and the training of cancer specialists of the future. Lombardi is one of only 41 comprehensive cancer centers in the nation, as designated by the National Cancer Institute, and the only one in the Washington, DC, area. For more information, go to http://lombardi.georgetown.edu.
About Georgetown University Medical Center
Georgetown University Medical Center is an internationally recognized academic medical center with a three-part mission of research, teaching and patient care (through Georgetown's affiliation with MedStar Health). GUMC's mission is carried out with a strong emphasis on public service and a dedication to the Catholic, Jesuit principle of cura personalis -- or "care of the whole person." The Medical Center includes the School of Medicine and the School of Nursing and Health Studies, both nationally ranked, the world-renowned Lombardi Comprehensive Cancer Center and the Biomedical Graduate Research Organization (BGRO), home to 60 percent of the university's sponsored research funding.