While Tamoxifen (Tam) has proven to be effective as a breast cancer prevention agent, Tam therapy onlyreduces the risk of developing breast cancer by ~50% in high risk women. Therefore, identification ofbiomarkers is essential to determine which women will benefit from Tam prevention. Recent studies suggestthat rapid non-classical hormone signaling may play an important role in normal mammary gland homeostasisthrough stimulation of extra nuclear targets and co-activator recruitment. We observe in breast cytologyspecimens from high-risk women that ER expression is elevated in only 20% of mammary atypia and low ERexpression in mammary atypia does not predict resistance to Tam prevention. We hypothesize that in womenwith mammary atypia, rapid non-classic signaling may play an important role regulating response to Tamprevention.PELP1 is a transcriptional nuclear activator of ER-signaling. Cytoplasmic expression of PELP1 in breastcancer cells triggers contitutive activation of AKT and results in Tam-resistance. Further, Dr. Seewaldt'slaboratory has demonstrated that Tam promotes apoptosis through the coordinated regulation of AKT-phosphorylation. The objective of my current research is to determine if PELP1 localization predicts responseto Tam. Here, I aim to test the hypothesis that cytoplasmic PELP1 promotes Tam-resistance, in part,through constitutive activation of AKT. The following Aims are proposed: 1) Does cytoplasmiclocalization of PELP1 in HMECs promote Tam-resistance through constitutive activation of Akt? 2) Doescytoplasmic PELP1 localization in atypical RPFNA cytological samples from high-risk women predictdysregulated AKT? 3) Does cytoplasmic PELP1 in atypical RPFNA predict cytological resistance to Tamprevention?

Public Health Relevance

Currently there are no good biomarkers that predict which women will get breast cancer or respond to chemoprevention therapies. The objective of this proposal is to determine if cytoplasmic localization of PELP1 predicts resistance to tamoxifen chemoprevention in women at high-risk for developing breast cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Academic/Teacher Award (ATA) (K07)
Project #
5K07CA131501-03
Application #
8209126
Study Section
Subcommittee G - Education (NCI)
Program Officer
Perkins, Susan N
Project Start
2010-09-01
Project End
2015-08-31
Budget Start
2011-09-01
Budget End
2012-08-31
Support Year
3
Fiscal Year
2011
Total Cost
$120,401
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Truong, Thu H; Hu, Hsiangyu; Temiz, Nuri A et al. (2018) Cancer Stem Cell Phenotypes in ER+ Breast Cancer Models Are Promoted by PELP1/AIB1 Complexes. Mol Cancer Res 16:707-719
Girard, Brian J; Knutson, Todd P; Kuker, Bethanie et al. (2017) Cytoplasmic Localization of Proline, Glutamic Acid, Leucine-rich Protein 1 (PELP1) Induces Breast Epithelial Cell Migration through Up-regulation of Inhibitor of ?B Kinase ? and Inflammatory Cross-talk with Macrophages. J Biol Chem 292:339-350
Girard, Brian J; Regan Anderson, Tarah M; Welch, Siya Lem et al. (2015) Cytoplasmic PELP1 and ERRgamma protect human mammary epithelial cells from Tam-induced cell death. PLoS One 10:e0121206
Daniel, A R; Gaviglio, A L; Knutson, T P et al. (2015) Progesterone receptor-B enhances estrogen responsiveness of breast cancer cells via scaffolding PELP1- and estrogen receptor-containing transcription complexes. Oncogene 34:506-15
Girard, Brian J; Daniel, Andrea R; Lange, Carol A et al. (2014) PELP1: a review of PELP1 interactions, signaling, and biology. Mol Cell Endocrinol 382:642-651