Dennis C. Sgroi, MD

Sgroi Lab

“Understanding the molecular genetic events associated with the pathogenesis of human breast cancer...”

Overview

Dennis C. Sgroi, MD

Professor of Pathology, Harvard Medical School
Executive Vice-Chair and Director of Breast Pathology, Massachusetts General Hospital

Molecular Pathology Unit
Massachusetts General Hospital
149 13th Street, 6th Floor
Charlestown, MA 02129
Phone: 617-726-5697
Fax: 617-726-5684
Email: dsgroi@mgh.harvard.edu

Overview

The overarching goals of research in the Sgroi laboratory are to develop better ways to identify patients who are at risk for the development of breast cancer and to identify those breast cancer patients who are likely to benefit from targeted drug therapies. We are taking several different approaches to achieving these goals. First, we are deciphering specific molecular events that occur during the earliest stages of tumor development and using this knowledge to develop biomarkers that will predict for increased risk of progression to cancer. Second, using advanced molecular technologies, we are searching for novel breast cancer biomarkers to identify patients with hormone-receptor-positive breast cancer who are most likely to benefit from extended hormonal therapy and from novel targeted therapeutics.


My research focuses on understanding the molecular genetic events associated with the pathogenesis of human breast cancer. My laboratory has developed technological approaches to study gene expression in the earliest microscopic precursor lesions as well as in the latest stages of human breast cancer. Specifically, we have been successful in combining laser capture microdissection, high-density cDNA arrays and real-time quantitative PCR and advanced tandem mass spectrometry technologies to identify novel gene and protein expression patterns in human breast cancer. We have shown that the various pathological stages of breast cancer progression are highly similar at the transcriptional level, and that atypical intraductal hyperplasia—the earliest identifiable stage of breast cancer—is a genetically advanced lesion with an expression profile that resembles that of invasive breast cancer. More recently, we have studied the gene expression changes of the stromal microenvironment during breast cancer progression, and we demonstrated that the transition from preinvasive to invasive breast cancer is associated with distinct stromal gene expression changes.


Presently, my laboratory is focused on applying high-throughput DNA microarray and proteomic technologies as a means to predict the clinical behavior of human breast cancer in the setting of hormonal and chemotherapeutic regimens. We have independently developed two complementary biomarkers—the Molecular Grade Index (MGI) and the HOXB13/IL17BR (H/I). MGI is a molecular surrogate for histological grade and a highly precise biomarker for risk of breast cancer recurrence. The HOXB13:IL17BR index is a biomarker of endocrine responsiveness in ER+ breast cancer, as it has been shown to predict for benefit from adjuvant and extended anti-hormonal therapy. Most recently, we demonstrated that the combination MGI and H/I, called the Breast Cancer Index (BCI), outperforms the Oncotype Dx Recurrence Score for predicting risk of recurrence.  As a result of our collective data, we anticipate assessing BCI in clinical trials of extended adjuvant hormonal therapy. Lastly, we are currently investigating the functional activity of HOXB13 and assessing its possible role as a surrogate marker for a nonclassical estrogen receptor signaling pathway.

 

Read the Bardeesy Lab's Annual Report in FullPathology logo and research brochure

Group Members

Stacy Francis, Lab Manager
Rachel Brooke, Research Technician I

Research Projects

Our research focuses on understanding the molecular genetic events associated with the pathogenesis of human breast cancer. My laboratory has developed technological approaches to study gene expression in the earliest microscopic precursor lesions as well as in the latest stages of human breast cancer. Specifically, we have been successful in combining laser capture microdissection, high-density cDNA array, and real-time quantitative PCR (RTQ-PCR) technologies to identify novel gene expression patterns in human breast cancer. Using this approach, we have demonstrated for the first time that atypical intraductal hyperplasia and ductal carcinoma in situ are direct precursors to invasive ductal carcinoma. More specifically, we have shown that the various pathological stages of breast cancer progression are highly similar at the transcriptional level, and that atypical intraductal hyperplasia—the earliest identifiable stage of breast cancer—is a genetically advanced lesion with an expression profile that resembles that of invasive breast cancer. More recently, we have studied the gene expression changes of the stromal microenvironment during breast cancer progression, and we have demonstrated that the transition from preinvasive to invasive breast cancer is associated with distinct stromal gene expression changes.

In collaboration with Barry Karger, PhD, of the Barnett Institute, we have used advanced tandem mass spectrometry to perform comparative proteomic profiling of normal breast epithelium with neoplastic epithelium of the preinvasive and invasive stages of breast cancer. Through a novel bioinformatic approach, we recently integrated our transcriptomic and proteomic data sets to identify a novel, robust biomarker of clinical outcome in estrogen-receptor-positive breast cancer patients. We are currently applying tandem mass spectometry technologies to standard formalin-fixed, paraffin-embedded breast tumor samples as a means to identify biomarkers of therapeutic response to HER2- and estrogen-receptor pathway-driven tumors.

Presently, my laboratory is focused on applying high-throughput DNA microarray and proteomic technologies as a means to predict the clinical behavior of human breast cancer in the setting of specific hormonal and chemotherapeutic regimens. We have independently developed two complementary biomarkers—the Molecular Grade Index (MGI) and the HOXB13/IL17BR (H/I). MGI is a molecular surrogate for histological grade and a highly precise biomarker for risk of breast cancer recurrence. The HOXB13:IL17BR index, on the other hand, is a biomarker of endocrine responsiveness in ER+ breast cancer, as it has been shown to predict for benefit from adjuvant tamoxifen and extended adjuvant aromatase inhibitor therapy. Most recently, we demonstrated that the combination MGI and H/I, called the Breast Cancer Index (BCI), outperforms the Oncotype Dx Recurrence Score for predicting risk of recurrence. As a result of our collective data, we anticipate assessing BCI in clinical trials of extended adjuvant hormonal therapy. Given that HOXB13 expression in clinical breast cancers is associated with endocrine therapy responsiveness, we are currently investigating the functional activity of HOXB13 and assessing its possible role as a surrogate marker for a nonclassical estrogen receptor signaling pathway.

Lastly, using an artificial zinc-finger transcription factors combinatorial library technology, we developed an in vitro breast cancer model of drug resistance to a clinically important antiendocrine therapeutic agent. Our results demonstrate that this approach can be used successfully to induce stable drug resistance in human cancer cell lines and to identify a gene expression signature that is associated with a clinically relevant drug-resistance phenotype. These experiments provide an important proof of principle for the use of combinatorial zinc-finger transcription factor libraries to induce and to study important cellular phenotypes, including human cancer drug resistance. We are currently using this approach to identify potential biomarkers for HER2-directed and PARP1-directed therapies.

 

Selected Publications

Bibliography of Dennis C. Sgroi via PubMed

McMullin RP, Wittner BS, Yang C, Denton-Schneider BR, Hicks D, Singavarapu R, Moulis S, Lee J, Akbari MR, Narod SA, Aldape  KD, Steeg PS, Ramaswamy S, and Sgroi DC. A BRCA1 deficient-like signature is enriched in breast cancer brain metastases and predicts DNA damage-induced PARP inhibitor sensitivity. Breast Cancer Res. 2014;16(2):R25.

Sgroi, DC, Sestak I, Cuzick J, Zhang Y, Schnabel CA, Schroeder B, Erlander MG, Dunbier A, Sidhu K, Lopez-Knowles E, Goss PE, and Dowsett M. Prediction of late distant recurrence in patients with oestrogen-receptor-positive breast cancer: a prospective comparison of the Breast Cancer Index (BCI) assay, 21-gene recurrence score, and IHC4 in TransATAC study population. Lancet Oncol. 2013;14(11):1067-76.

Sgroi DC, Carney E, Zarrella E, Steffel L, Binns SN, Finkelstein DM, Szymonifka J, Bhan AK, Shepherd LE, Zhang Y, Schnabel CA, Erlander MG, Ingle JN, Porter P, Muss HB, Pritchard KI, Tu D, Rimm DL, Goss PE. Prediction of late disease recurrence and extended adjuvant letrozole benefit by the HOXB13/IL17BR biomarker. J Natl Cancer Inst. 2013;105:1036-1042.

Zhang Y, Schnabel CA, Schroeder BE, Jerevall PL, Jankowitz RC, Fornander T, Stal O, Brufsky AM, Sgroi D, Erlander M. Breast cancer index identifies early stage ER+ breast cancer patients at risk for early and late distant recurrence. Clin Cancer Res. 2013;19(15):4196-205

Imielinski M, Cha S, Rejtar T, Richardson EA, Karger BL, Sgroi DC. Integrated proteomic, transcriptomic, and biological network analysis of breast carcinoma reveals molecular features of tumorigenesis and clinical relapse. Mol Cell Proteomics. 2012

Contact

Contact Us

Sgroi Laboratory

Massachusetts General Hospital

149 13th Street, Room 7139Molecular Pathology Unit Charlestown, MA 02129
  • Phone: 617-726-5697
  • Fax: 617-726-5684

Email: dsgroi@partners.org

Back to Top