University of Pittsburgh Cancer Institute (UPCI)

Basic Cancer Biology

Laboratory ResearchBasic biology research within the BOCP includes molecular and cellular studies using cell lines and animal models. A major aim is to investigate and discover new molecular and cellular mechanisms of cancer initiation and progression, with the goal of identifying dependencies that can be targeted using new or repurposed drugs. This work is being performed in close collaboration with the Molecular and Cellular Cancer Biology Program (MCCBP) and the Cancer Therapeutics Program (CTP).

Selected Publications

  • Recent retrospective analyses suggest that patients with invasive lobular carcinoma (ILC) receiving adjuvant endocrine therapy may not benefit as much as patients with invasive ductal carcinoma. On the basis of these observations, we characterized ER function and endocrine response in ILC models. Our observation that ER drives a unique program of gene expression in ILC cells correlates with the ability of tamoxifen to induce growth in these cells. Targeting growth factors using FGFR1 inhibitors may block survival pathways required by ILC and reverse tamoxifen resistance. (Sikora et al., Cancer Research. 74(5):1463-74, 2014).
  • Profilin 1 (Pfn1), a ubiquitously expressed actin-binding protein, has an indispensable role in migration and proliferation of normal cells, but is unpredictably downregulated in breast cancer. Reduction of Pfn1 in breast cancer cells caused hypermotility through a PI(3,4)P(2) signaling axis, and resulted in increased migration and dissemination of cells from a xenograft tumor. Contrasting these dissemination promoting activities, loss of Pfn1, however, dramatically inhibits metastatic outgrowth of disseminated breast cancer cells, suggesting that Pfn1 has a key role in the metastatic colonization process. (Ding et al., Oncogene. May 2013.)
  • Treatment of breast cancer cells with histone deacetylase (HDAC) inhibitors caused an increase in histone methylation (H3K4me2), a key mark of transcriptional activation and a substrate of lysine demethylase 1 (LSD1). Reduction of LSD1 caused an increase in histone acetylation, suggesting dynamic crosstalk between histone methylation and acetylation. Importantly, treatment of cells with both HDAC and histone demethylase (HDM) inhibitors caused a synergistic inhibition of cell growth (Huang et al., Breast Cancer Res Treat. 131(3):777-89, 2012), and the molecular mechanism for this effect was due to re-expression of a number of tumor suppressors (Vasilatos et al., Carcinogenesis. 34(6):1196-207, 2013).
  • In a cohort of ovarian cancer patients on a phase 2 trial of intraperitoneal interleukin-2, increased serum levels of MUC1 (a tumor associated antigen and oncoprotein) and high anti-MUC1 antibody levels were associated with poor clinical response and reduced overall survival (Budiu et al., Cancer Immunol Immunother. 60(7):975-84, 2011). To examine MUC1 immunobiology in ovarian cancer further, a preclinical triple transgenic model (MUC1+/-; loxP-Stop-loxP-K-ras(G12D/+); PTENloxP/loxP) was developed, which when injected with adenoviral cre, results in MUC1-positive ovarian cancer. Vaccination of MUC1KrasPten mice with type 1 polarized dendritic cells loaded with a MUC1 peptide circumvented tumor-mediated immune suppression and prolonged survival (Budiu et al., Oncogene. 32(32):3664-75, 2013).

Members

Bhargava, Rohit, MD
Pathology
McAuliffe, Priscilla, MD, PhD
Surgery
Brufsky, Adam, MD, PhD
Medicine
Neumann, Carola, MD
Pharmacology & Chemical Biology
Chandran, Uma, PhD, MSIS
Biomedical Informatics (DBMI)
Oesterreich, Steffi, PhD
Pharmacology & Chemical Biology
Dabbs, David, MD
Pathology
Puhalla, Shannon, MD
Medicine
Davidson, Nancy, MD
Medicine
Rajkovic, Aleksandar, MD, PhD
Obstetrics, Gynecology & Reproductive Sciences
Donnenberg, Vera, PhD
Surgery
Roy, Partha, PhD
Bioengineering
Edwards, Robert, MD
Obstetrics, Gynecology & Reproductive Sciences
Singh, Shivendra, PhD
Pharmacology & Chemical Biology
Elishaev, Esther, MD
Pathology
Steinman, Richard, MD, PhD
Medicine
Huang, Xin, PhD
Obstetrics, Gynecology & Reproductive Sciences
Vlad, Anda, MD, PhD
Obstetrics, Gynecology & Reproductive Sciences
Huang, Yi, PhD
Pharmacology & Chemical Biology
Zhang, Mei, PhD
Developmental Biology
Lee, Adrian, PhD
Pharmacology & Chemical Biology