Associate Research Professor
Department of Pathology and Laboratory Medicine
Development of Tools for Prognostication in Breast Carcinoma
1. Three-gene signature for DCIS patients to assess risk of development of invasive breast cancer Breast cancer is thought to develop through a stepwise progression of disease. Initial events are believed to occur inside the ducts (intra-ductal) followed by invasion at later stages. These early intra-ductal events tend to be associated with calcifications, which can be detected by mammography. The routine use of mammographic screening has resulted in increased incidence of Ductal carcinoma in situ (DCIS), the most common type of pre-invasive lesion. DCIS, if left untreated, will progress to invasive carcinoma in around 30% of patients. As factors associated with progression to invasive carcinoma or recurrence of DCIS are not well identified, all patients are treated with “standard of care” therapy consisting of surgery followed by radiotherapy and/or endocrine therapy. This results in overtreatment of at least 70% of patients. These ineffective therapies lead to unnecessary toxicities such as second cancers, physical, socioeconomic and psychological burden, but no benefit. There is a great need to identify women who will not recur or progress to invasive carcinoma, so that these women are not overdiagnosed and overtreated with unnecessary treatments and suffer from associated side effects. Identification of the bad players will also enable elucidation of determinants of breast cancer initiation, risk, or susceptibility and design of precision therapies for the population at high risk of recurrence. Invention: We developed a 3- gene expression signature that can stratify patients based on the risk of development of invasive disease breast carcinoma in DCIS. (in collaboration with Drs. Badve, Dundar and Ginty). The performance of the 3-gene signature was superior to Oncotype DCIS score in these cohorts, the current gene signature in the market. This study, to our knowledge, provides the first comprehensive transcriptomic analysis of pure DCIS cases with and without INV-BC. We developed a 3-gene algorithm, which had an AUC of 0.833 in the independent validation cohort and correctly identified all the patients who developed invasive breast carcinoma. Translational Relevance: The developed 3-gene signature identifies cases likely to progress to invasive breast carcinoma with high accuracy and will serve as a stratifying factor to improve the management of patients with DCIS. It will specifically identify women at high risk for development of invasive cancer for therapeutic targeting, while reduce overdiagnosis and prevent overtreatment, and preventing morbidity and mortality associated with breast cancer. BIOMARKERS FOR RISK OF DCIS RECURRENCE IU Reference Number: 2020-109-01; Application Number: 63/130,262 Filing Date: December 23, 2020 Inventors: Sunil Badve, Yesim Gokmen-Polar, Murat Dundar. Summary: Development of a 3-gene signature for prognostication of DCIS 2. Characterization of Prognostic/Therapeutic Targets in Breast Cancer My research uses NextGen Technologies and microarrays to understand the transcriptional regulation by RNA that contribute to breast cancer progression. The utilization of next-generation sequencing technologies has further revealed the importance of alternative splicing in cancer including breast cancer. My work demonstrated a prognostic role for SF3B3, Splicing factor 3b, subunit 3, in endocrine resistance of ER-positive breast cancer. For the first time, my team identified the epithelial splicing regulatory protein 1 (ESRP1), an RNA-binding protein and splicing factor, as a marker of poor prognosis in ER‐positive breast cancer. ESRP1 is known to regulate epithelial‐to‐mesenchymal transition (EMT) by modifying alternative splicing events. Our findings demonstrated that ESRP1 modulates growth without triggering EMT, and acts as a novel regulator of metabolic pathways in tamoxifen-resistant breast cancer ((EMBO Reports 2019 e46078DOI 10.15252/embr.201846078). These results are very relevant to the clinical setting in advance ER+ breast cancer. Translational Relevance: Obesity has been previously associated with inferior outcomes in hormone receptor-positive operable breast cancer. This work provides a molecular evidence for the role of altered metabolism in determining adverse prognosis of ER+ breast cancer via the control of ESRP1, a splicing factor and a novel therapeutic targeting for endocrine-resistant ER+ breast cancer.