R01CA271498

Next Generation Rat Models of ER+ Breast Cancer

Title: Next Generation Rat Models of ER+ Breast Cancer

Abstract:
Despite the prevalence of estrogen receptor-positive (ER+) breast cancer (BCA), there are no mammalian models that are immunocompetent and metastasize spontaneously to clinically relevant organs such as bones. ER+ BCA comprises approximately 70% of BCA cases and is treated with surgical resection and adjuvant endocrine therapies. Although the 5-year survival rate is high, the risk of metastatic recurrence persists for decades, and 20-40% of ER+ BCA patients eventually succumb to metastatic disease, most often in bones.

Our limited knowledge of ER+ BCA has been largely derived from oversimplified cell line models and in vitro experiments. Our available xenograft models exclude the critical immune component, while genetically engineered mouse models (GEMMs) rarely stably maintain ER expression and rely on ER signaling – and none metastasize to bone, the most frequent site. As a result, very little is known about the initial tumorigenesis process and bone metastasis of ER+ BCA, which greatly impedes our effort to develop new prevention strategies or adjuvant therapeutics that can block/treat ER+ BCA bone metastasis.

We have developed a series of rat ER+ BCA models by intraductal injection of viruses to introduce genetic alterations. Our preliminary data demonstrated that these rat ER+ mammary tumors: 1) developed in immunocompetent hosts, 2) showed endocrine therapy sensitivity or resistance, and 3) readily formed ER+ metastases, including in bone – all of which are key properties that are lacking in existing BCA models.

Based on these, we hypothesize that rat-based intraductal injection models (RIIMs) of breast cancer faithfully recapitulate human ER+ BCA in terms of tumor initiation, metastasis, and therapeutic responses. We will pursue the following three aims:

(1) To characterize early progression of ER+ BCA in RIIM models.

(2) To characterize the metastatic behaviors of ER+ BCA in RIIM models.

(3) To credential ER+ RIIM models in recapitulating therapeutic responses and resistance mechanisms of human ER+ BCA.

Baylor College Of Medicine

TO PROVIDE FUNDAMENTAL INFORMATION ON THE CAUSE AND NATURE OF CANCER IN PEOPLE, WITH THE EXPECTATION THAT THIS WILL RESULT IN BETTER METHODS OF PREVENTION, DETECTION AND DIAGNOSIS, AND TREATMENT OF NEOPLASTIC DISEASES. CANCER BIOLOGY RESEARCH INCLUDES THE FOLLOWING RESEARCH PROGRAMS: CANCER CELL BIOLOGY, CANCER IMMUNOLOGY, HEMATOLOGY AND ETIOLOGY, DNA AND CHROMOSOMAL ABERRATIONS, TUMOR BIOLOGY AND METASTASIS, AND STRUCTURAL BIOLOGY AND MOLECULAR APPLICATIONS.

93.396 - Cancer Biology Research

National Cancer Institute (NCI) [HHS - NIH]

Houston, Texas 770303411 United States

Single Zip Code

Research Projects to Enhance Applicability of Mammalian Models for Translational Research (R01 Clinical Trial Not Allowed) (PAR-20-131)

Amendment Since initial award the total obligations have increased 411% from $612,175 to $3,130,984.