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.
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.
|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|
|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|
|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|
|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|
|Witkiewicz, A K; Cox, D W; Rivadeneira, D et al. (2014) The retinoblastoma tumor suppressor pathway modulates the invasiveness of ErbB2-positive breast cancer. Oncogene 33:3980-91|
|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|
|Knudsen, Erik S; Dervishaj, Ornella; Kleer, Celina G et al. (2013) EZH2 and ALDH1 expression in ductal carcinoma in situ: complex association with recurrence and progression to invasive breast cancer. Cell Cycle 12:2042-50|
|Witkiewicz, Agnieszka K; Ertel, Adam; McFalls, Jeanne et al. (2012) RB-pathway disruption is associated with improved response to neoadjuvant chemotherapy in breast cancer. Clin Cancer Res 18:5110-22|
|Knudsen, Erik S; Pajak, Thomas F; Qeenan, Maria et al. (2012) Retinoblastoma and phosphate and tensin homolog tumor suppressors: impact on ductal carcinoma in situ progression. J Natl Cancer Inst 104:1825-36|