A Novel Mouse Model for SNP in Steroid Receptor Co-Activator-1 Reveals Role in Bone Density and Breast Cancer Metastasis
Abstract
The steroid receptor coactivator-1 (SRC-1) is a nuclear receptor co-activator, known to play key roles in both estrogen response in bone and in breast cancer metastases. We previously demonstrated that the P1272S single nucleotide polymorphism (SNP; P1272S; rs1804645) in SRC-1 decreases the activity of estrogen receptor in the presence of selective estrogen receptor modulators (SERMs) and that it is associated with a decrease in bone mineral density (BMD) after tamoxifen therapy, suggesting it may disrupt the agonist action of tamoxifen. Given such dual roles of SRC-1 in the bone microenvironment and in tumor cell-intrinsic phenotypes, we hypothesized that SRC-1 and a naturally occurring genetic variant, P1272S, may promote breast cancer bone metastases. We developed a syngeneic, knock-in mouse model to study if the SRC-1 SNP is critical for normal bone homeostasis and bone metastasis. Our data surprisingly reveal that the homozygous SRC-1 SNP knock-in increases tamoxifen-induced bone protection after ovariectomy. The presence of the SRC-1 SNP in mammary glands resulted in decreased expression levels of SRC-1 and reduced tumor burden after orthotopic injection of breast cancer cells not bearing the SRC-1 SNP, but increased metastases to the lungs in our syngeneic mouse model. Interestingly, the P1272S SNP identified in a small, exploratory cohort of bone metastases from breast cancer patients was significantly associated with earlier development of bone metastasis. This study demonstrates the importance of the P1272S SNP in both the effect of SERMs on BMD and the development of tumor in the bone.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- May 07, 2021
- Source ID
- 10.1210/endocr/bqab094
Entities
People
- Adrian V Lee
- Alejandro Morales-restrepo
- Benjamin M Martin
- Brendan Lee
- Deborah L Galson
- Feiqi Lu
- Geoffrey Pecar
- George C. Tseng
- Kostas Verdelis
- Kurt R Weiss
- Li Zhu
- Lyuda Lukashova
- Margaret Hankins
- Peter C. Lucas
- Peter G Alexander
- Peter Mittwede
- Rebecca J. Watters
- Ryan J. Hartmaier
- Shiming Jiang
- Steffi Oesterreich
- Yuqing Chen
Organizations
- Baylor College of Medicine
- National Institute of Arthritis and Musculoskeletal and Skin Diseases
- National Institute of Diabetes and Digestive and Kidney Diseases
- Tsinghua University
- United States Department of Defense
- University of Pittsburgh
- University of Pittsburgh Cancer Institute
- University of Pittsburgh School of Medicine