Abstract

Currently ductal carcinoma in situ (DCIS) accounts for 20-30% of newly diagnosed breast cancers in screened populations. Because of the inability to stratify the DCIS populations at high risk for recurrence and disease progression, many women are currently over-treated and approximately 10-15% patients have disease recurrence despite surgical and adjuvant interventions. Preliminary and published data indicate that a large fraction of DCIS lesions exhibits alterations in the ErbB2 and RB-pathways. However there are no studies investigating effects of both pathways abnormalities in the same DCIS lesion. In this application we using functional studies, will: 1. Define role of RB pathway in progression of ErbB2 overexpressing DCIS and 2. Determine how RB and ErbB2 status impacts response to radiation therapy.

Public Health Relevance

By improving our understating of mechanism driving progression of DCIS to invasive breast cancer the proposed studies will allow for better prognostic stratification of DCIS patients. Additionally we will investigate approaches to treat DCIS rationally based on knowledge of RB and ErbB2 pathways.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA163863-06
Application #
9071392
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Lively, Tracy (LUGO)
Project Start
2012-08-16
Project End
2017-05-31
Budget Start
2016-06-01
Budget End
2017-05-31
Support Year
6
Fiscal Year
2016
Total Cost
$327,957
Indirect Cost
$114,304

  Institution

Name
University of Arizona
Department
Pathology
Type
Schools of Medicine
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721

  Publications

Witkiewicz, Agnieszka K; Chung, Sejin; Brough, Rachel et al. (2018) Targeting the Vulnerability of RB Tumor Suppressor Loss in Triple-Negative Breast Cancer. Cell Rep 22:1185-1199
Knudsen, Erik S; Witkiewicz, Agnieszka K (2017) The Strange Case of CDK4/6 Inhibitors: Mechanisms, Resistance, and Combination Strategies. Trends Cancer 3:39-55
Knudsen, Erik S; Hutcheson, Jack; Vail, Paris et al. (2017) Biological specificity of CDK4/6 inhibitors: dose response relationship, in vivo signaling, and composite response signature. Oncotarget 8:43678-43691
Knudsen, Erik S; Witkiewicz, Agnieszka K (2016) Defining the transcriptional and biological response to CDK4/6 inhibition in relation to ER+/HER2- breast cancer. Oncotarget 7:69111-69123
Bendris, Nawal; Stearns, Carrie J S; Reis, Carlos R et al. (2016) Sorting nexin 9 negatively regulates invadopodia formation and function in cancer cells. J Cell Sci 129:2804-16
Knudsen, Erik S; McClendon, A Kathleen; Franco, Jorge et al. (2015) RB loss contributes to aggressive tumor phenotypes in MYC-driven triple negative breast cancer. Cell Cycle 14:109-22
Asghar, Uzma; Witkiewicz, Agnieszka K; Turner, Nicholas C et al. (2015) The history and future of targeting cyclin-dependent kinases in cancer therapy. Nat Rev Drug Discov 14:130-46
Witkiewicz, Agnieszka K; Cox, Derek; Knudsen, Erik S (2014) CDK4/6 inhibition provides a potent adjunct to Her2-targeted therapies in preclinical breast cancer models. Genes Cancer 5:261-72
Witkiewicz, Agnieszka K; Balaji, Uthra; Knudsen, Erik S (2014) Systematically defining single-gene determinants of response to neoadjuvant chemotherapy reveals specific biomarkers. Clin Cancer Res 20:4837-48
Witkiewicz, Agnieszka K; Knudsen, Erik S (2014) Retinoblastoma tumor suppressor pathway in breast cancer: prognosis, precision medicine, and therapeutic interventions. Breast Cancer Res 16:207

Showing the most recent 10 out of 14 publications