The incidence of breast cancer is high, with 1 in 8 women in the U.S. developing this disease over the course of their lifetime. Taxanes are potent chemotherapeutic agents that are a standard component of early and metastatic breast cancer treatment strategies. Despite major therapeutic advances, progression of tumors and taxane resistance continue to be major clinical problems that promote breast cancer mortality. The clinical application of biomarkers have greatly reduced the mortality rates associated with breast cancer;however, there is an urgent need for novel biomarkers that can more effectively identify patients who are 1) at risk for advanced breast cancer progression or 2) resistant to taxane therapy. Using a candidate approach, we sought to investigate the role of neuronal calcium sensor-1 (NCS-1) in breast cancer. NCS-1 (a novel binding partner of the taxane, paclitaxel) has been shown to act as a survival factor in neurons by activating the Phosphoinositide 3- kinase (PI3K)/ Protein Kinase B (AKT) signaling pathway. Our central hypothesis is that NCS-1 promotes breast cancer progression and taxane resistance by altering cancer signaling networks. This hypothesis is based on the functional characterization of NCS-1, in neuronal and neuroendocrine models, as well as our preliminary data. Using immunohistochemistry (IHC) and our novel Automated Quantitative Analysis (AQUA) technology, we quantified the expression of NCS-1 in 619 cases of primary breast carcinomas. We found that NCS-1 was expressed in a cohort of breast cancer patients and significantly correlates with poor clinical outcome independent of Estrogen Receptor (ER), Human Epidermal Growth Factor 2 Receptor (HER-2), and lymph node status. The objectives of our study are to 1) investigate the role of NCS-1 in the molecular mechanisms governing breast cancer progression and taxane resistance and to 2) assess the clinical utility of NCS-1 as a novel predictive/ prognostic breast cancer biomarker. Elucidating the role of NCS-1 in breast cancer progression and taxane resistance may broaden our understanding of these processes and establish NCS-1 as a novel molecular target for future therapeutic intervention. Furthermore, findings from our study may validate NCS-1 as a novel predictive/ prognostic breast cancer biomarker, which may ultimately increase breast cancer survival through individualization of patient care.

Public Health Relevance

Breast cancer is one of the leading causes of death among women world-wide[1]. The application of biomarkers has helped reduced breast cancer mortality rates;however, new biomarkers are urgently needed. This project will investigate the role of Neuronal Calcium Sensor-1 (NCS-1) in breast cancer progression and chemotherapeutic resistance;through our findings we aim to establish NCS-1 as a novel predictive/prognostic biomarker.

Agency
National Institute of Health (NIH)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
3F31CA183571-01S1
Application #
8878425
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Vallejo-Estrada, Yolanda
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Yale University
Department
Pathology
Type
Schools of Medicine
DUNS #
City
New Haven
State
CT
Country
United States
Zip Code
06510