SPOREs : Organ-Specific SPORE Programs : Breast

Dana-Farber/Harvard Breast Cancer SPORE

J. Dirk Iglehart, MD, Principal Investigator
Dana-Farber Cancer Institute
44 Binney Street
Boston, MA 02115
Tel: 617-632-5744
Fax: 617-632-3709

www.dfhcc.harvard.edu/spores/breast

The Dana-Farber/Harvard SPORE in Breast Cancer (Breast SPORE) is entering its ninth year of funding. The SPORE features five research projects, five cores, a developmental project program, a career development program and several NCI-Avon Progress for Patients supplements. The SPORE is an integral component of the Dana-Farber/Harvard Cancer Center (DF/HCC) and represents significant translational research collaboration in breast cancer.

The Projects in the Breast SPORE fall into two broad categories:

• Projects starting with treatments:
  • BRCA1-associated and basal-like breast cancer
  • Combination therapy for HER2-positive breast cancer
  • Co-activators of the estrogen receptor and resistance to endocrine therapy
• Projects starting with tissues:
  • The influence of tumor-stromal cell interactions
  • Discovering susceptibility factors by interactions between functional screening and population studies

The Cores deliver the benefits of efficiencies to the Projects, as well as to the other Cores, by centralizing these specific functions and responsibilities; it allows the Breast SPORE to effectively leverage its resources.

• Tissue and Pathology
• Clinical Studies
• Cohort Studies and Databases
• Biostatistics and Bioinformatics
• Communication, Planning and Administration

PROJECTS:

BRCA1-ASSOCIATED AND BASAL-LIKE BREAST CANCER

• Aim 1: Compare the molecular phenotypes of BLC and BRCA1-mutant breast cancers.
• Aim 2: Identify specific functional defects in DNA repair in BLC using DNA repair assays in viable tumor cells obtained from clinical samples.
• Aim 3: Access the response of a cohort of ER (-), PR (-), Her2 (-) breast cancers to cis-platinum in a phase II neo-adjuvant clinical trial and determine if results of informative assays developed above correlate with clinical response.

Recent Publications:

Garber JE, Richardson A, Harris LN, Miron A, Silver D, Golshan M, Ryan PD, Ganesan S, Li X, Wang ZC, Clarke K, Tung N, Iglehart JD, Winer EP. Neoadjuvant Cis-Platin® (CDDP) in Triple-Negative Breast Cancer (BC). 29th Annual San Antonio Breast Cancer Symposium, 2006.

Wang ZC, Silver DM, Chang SB, Lu X, Kim JY, Richardson AL, Iglehart JD. Distinct patterns of chromosomal alterations characterize the subtypes of breast cancer, implying different mechanisms of chromosomal instability and support a new function of BRCA1 in tumor suppression. (Manuscript in preparation)

Michaela J. Kandel, Rebecca Gelman, Zsofia K. Stadler, Anthony Martyniak, Serena Masciari, Laura Collins, Andrea L. Richardson, Lyndsay N. Harris, Alexander Miron, Stuart Schnitt, Judy E. Garber. Prevalence of BRCA1 Mutations in Triple Negative Breast Cancer (Manuscript submitted, J Clin Oncol)

COMBINATION THERAPY FOR HER2-POSITIVE BREAST CANCER:

• Aim 1. Evaluate biomarkers of sensitivity and resistance to HER2-directed therapy
• Aim 2. Evaluate combinations of trastuzumab and signaling inhibitors
• Aim 3. Conduct unbiased screens for targets whose inhibition sensitizes to HER2-directed treatments

Recent Publications:

Zhao, J.J., Cheng, H. Jia,SD, Wang, L., Gjoerup, OV., Mikiami, A. and Roberts, T.M. (2006) The p110α isoform of PI3K is essential for proper growth factor signaling and oncogenic transformation. Proc Natl Acad Sci USA 103(44):16296-16300.

Zhao, J.J. and Roberts, T.M. (2006) PI3 Kinases in Cancer: From Oncogene Artifact to Leading Cancer Target. Sci. STKE 2006, 365: pe52.

Gjoerup OJ, Wu J, Chandler-Militello D, William GL, Zhao JJ, Jat PS and Roberts TM. A surveillance mechanism linking Bub1 loss to p53 activation. Proc Natl Acad Sci U S A, 2007; 104: 8334-8339.

Utermark T, Roberts TM and Zhao JJ. The requirement for the p110α isoform of PI3K in Polyoma middle T antigen mediated transformation. J. Virology, 2007; 81(13):7069-707.

Boehm JS, Zhao JJ*, Yao J, Kim SY, Dunn IF, Sjostrom AK, Garraway LA, Weremowicz, S, Stewart, CJ, Mulvey LA, Hill DE, Vidal M, Grenier J, Hinkle G, Root DE, Roberts TM, Lander ES, Polyak K and Hahn W. Integrative genomic approaches identify IKBKE as a breast cancer oncogene. Cell, 2007; 129:1065-1079. * Co-first and Co-corresponding author.

Jia S, Liu Z, Zhang S, Liu P, Lee S, Zhang J, Lee S, Zhang J, Signoretti S, Loda M, and Roberts TM, and Zhao JJ. Essential roles for the p110beta isoform of PI3K in cell growth, metabolism and tumorignensis. Nature, 2008, in press. Submitted to PMC, NIHMSID 56189.

CO-ACTIVATORS OF THE ESTROGEN RECEPTOR AND RESISTANCE TO ENDOCRINE THERAPY

• Aim 1. Determine the function of AIB1 and other coregulators in altering ER activity in breast cancer cells in culture under low estrogen conditions.
• Aim 2. Study the role of AIB1 and its interaction with growth factor signaling pathways in mediating the response to AIs in a transgenic mouse model.
• Aim 3. Perform brief exposure pre-surgical trials of AIs in postmenopausal women with newly diagnosed ER+ breast cancer.

RECENT PUBLICATIONS:

Eeckhoute, J., Keeton, E.K., Lupien, M., Krum, S.A.,Carroll, J.S., Brown, M. A positive cross-regulatory loop ties GATA-3 to estrogen receptor α expression in breast cancer. Cancer Res 2007 Jul 1;67(13):6477-83.

Frietze, S., Lupien, M., Silver, P.A., and Brown, M. CARM1 regulates estrogen stimulated breast cancer growth through the regulation of E2F1. Cancer Res 2008 Jan 1;68(1):301-6.

Lupien, M., Eeckhoute, J., Meyer, C.A., Wang, Q., Zhang, Y., Li, W., Carroll, J.S., Liu, X.S. and Brown, M. FoxA1 translates epigenetic signatures into enhancer driven lineage-specific transcription. Cell, 132 (6): 958-70, 2008.

THE INFLUENCE OF TUMOR-STROMAL INTERACTIONS

• Aim 1. To determine if stromal cells from uninvolved breast tissue from patients with breast cancer are more conducive to cancer development than stromal cells of women without cancer.
• Aim 2. To identify gene expression signatures of stromal cells associated with cancer, stromal cells from uninvolved breast tissue from patients with breast cancer, and stromal cells from breasts without cancer.
• Aim 3. To determine in human breast tissue samples if there is an association between stromal markers and epithelial lesions associated with increased breast cancer risk, and to determine if there are stromal markers that can be used as independent risk indicators

Recent Publications:

Kleer C, Bloushtain-Qimron N, Chen Y-H, Carrasco D, Hu M, Kraeft SK, Collins LC, Sabel MS, Rebecca Gelman R, Krop IE, Schnitt S, Kornelia Polyak K. Epithelial and stromal Cathepsin K and CXCL14 expression in breast tumor progression. Clin Can Res, in press

Boehm JB*, Zhao J*, Yao J*, Kim SY, Dunn IF, Sjostrom SK, Garraway LA, Weremowicz S, Greulich H, Stewart CJ, Mulvey LA, Ambrogio L, Hill DE, Vidal M, Meyerson M, Grenier J, Hinkle G, Root DE, Roberts TM, Lander ES, Polyak K*, Hahn WC*. Integrative genomic approaches identify IKBKE as a breast cancer oncogene. *indicates equal first and senior authors, respectively. Cell 2007; 129:1065-1079.

Hu M, Yao, J, Carroll DK, Weremowicz S, Chen H, Carrassco DE, Richardson AL, Violette S, Nikolskaya T, Nikolsky Y, Bauerlein EL, William C. Hahn WC, Gelman RS, Allred C, Bissell MJ, Schnitt SJ, Polyak K. Regulation of in situ to invasive breast carcinoma transition. Cancer Cell 2008; 13:394-406.

Hu M and Polyak K. Microenvironmental regulation of cancer development.

Curr. Op. Genet. Dev. 2007; 18:1-8

Campbell LL and Polyak K. Breast Tumor Heterogeneity: Cancer stem cells or clonal evolution? Cell Cycle 2007; 6:2332-2338.

Polyak K. Breast cancer stem cells: a case of mistaken identity? Stem Cell Rev 2007; 3:107-109.

Polyak K. Breast cancer: origins and evolution, J Clin Inv 2007; 117:3155-3163.

DISCOVERING SUSCEPTIBILITY FACTORS BY INTERACTIONS BETWEEN FUNCTIONAL SCREENING AND POPULATION STUDIES

• Aim 1. Examine if common genetic variants of EGF-R, ERBB2, CSF-1R and IGF-1R are associated with increased risk of breast cancer.
• Aim 2. Examine if rare variants of EGF-R, ERBB2, CSF-1R, and IGF-1R display distinct functional activities and if so, whether they are associated with familial breast cancer.
• Aim 3. Protein expression status in tissue microarrays of breast cancer tumors.
• Aim 4. Plasma levels of protein ligands are associated with subsequent breast cancer risk.

Recent Publications:

Tamimi RM, Byrne C, Colditz GA, Hankinson SE. Endogenous hormone levels, mammographic density, and subsequent risk of breast cancer in postmenopausal women. J Natl Cancer Inst 2007;99(15):1178-87.

Tamimi RM, Brugge JS, Freedman ML, Miron A, Iglehart JD, Colditz GA, et al. Circulating colony stimulating factor-1 and breast cancer risk. Cancer Res 2008;68(1):18-21.

Tamimi RM, Cox D, Kraft P, Colditz GA, Hankinson SE, Hunter DJ. Breast cancer susceptibility loci and mammographic density (under review).

CORES:

TISSUE AND PATHOLOGY

This Core maintains the SPORE Core Blood Repository (SCBR) to collect, process, annotate, store and distribute blood-derived samples from consented breast cancer patients seen at our SPORE-affiliated institutions. Whole blood, plasma, serum and buffy coats (lymphocytes) are the various components currently stored in the bank. A bar-coding system is employed to interface with our STIP (Specimen Tracking and Inventory Program) database system.

The SPORE repository also includes a frozen specimen bank that collects fresh breast tumor and matched normal tissues, normal breast tissues from reduction mammoplasties, and metastatic breast cancer specimens. These samples are provided to investigators as fresh tissue for cell sorting or tissue culture experiments, as frozen tissue or frozen sections, or as extracted DNA, RNA or protein. The processing and annotation of these specimens is a key role of the SPORE tissue repository. Approximately 200 breast tumor samples are currently in paraffin block tissue microarrays. These samples have matched frozen tissue, pathology annotation, clinical outcome annotation, and gene expression array profile data while a portion of these samples have SNP array genomic profile data. In addition, the repository collects, stores, and processes breast core biopsy samples, and surgical samples, in conjunction with SPORE and DFCI therapeutic trials

Recent Publications:

Bell DW, Kim SH, Godwin AK, Schiripo TA, Harris PL, Haserlat SM, Wahrer DC, Haiman CA, Daly MB, Niendorf KB, Smith MR, Sgroi DC, Garber JE, Olopade OI, Le Marchand L, Henderson BE, Altshuler D, Haber DA, and Freedman ML: Genetic and functional analysis of CHEK2 (CHK2) variants in multiethnic cohorts. Int J Cancer 2007, 121: 2661-2667

DeYoung MP, Horak P, Sofer A, Sgroi D, and Ellisen LW: Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling. Genes Dev 2008, 22: 239-251

Harris LN, You F, Schnitt SJ, Witkiewicz A, Lu X, Sgroi D, Ryan PD, Come SE, Burstein HJ, Lesnikoski BA, Kamma M, Friedman PN, Gelman R, Iglehart JD, and Winer EP: Predictors of resistance to preoperative trastuzumab and vinorelbine for HER2-positive early breast cancer. Clin Cancer Res 2007, 13: 1198-1207

Leong CO, Vidnovic N, DeYoung MP, Sgroi D, and Ellisen LW: The p63/p73 network mediates chemosensitivity to cisplatin in a biologically defined subset of primary breast cancers. J Clin Invest 2007, 117: 1370-1380

Ma XJ, Salunga R, Dahiya S, Wang W, Carney E, Durbecq V, Harris A, Goss P, Sotiriou C, Erlander M, and Sgroi D: A Five-Gene Molecular Grade Index and HOXB13:IL17BR Are Complementary Prognostic Factors in Early Stage Breast Cancer. Clin Cancer Res 2008, 14: 2601-2608

Wang Z, Dahiya S, Provencher H, Muir B, Carney E, Coser K, Shioda T, Ma XJ, and Sgroi DC: The prognostic biomarkers HOXB13, IL17BR, and CHDH are regulated by estrogen in breast cancer. Clin Cancer Res 2007, 13: 6327-6334

Wittner BS, Sgroi DC, Ryan PD, Bruinsma TJ, Glas AM, Male A, Dahiya S, Habin K, Bernards R, Haber DA, Van't Veer LJ, and Ramaswamy S: Analysis of the MammaPrint Breast Cancer Assay in a Predominantly Postmenopausal Cohort. Clin Cancer Res 2008, 14: 2988-2993

Hu M, Yao J, Carroll DK, Weremowicz S, Chen H, Carrasco D, Richardson A, Violette S, Nikolskaya T, Nikolsky Y, Bauerlein EL, Hahn WC, Gelman RS, Allred C, Bissell MJ, Schnitt S, Polyak K. Regulation of in situ to invasive breast carcinoma transition. Cancer Cell. 2008 May;13(5):394-406.

Overholtzer M, Mailleux AA, Mouneimne G, Normand G, Schnitt SJ, King RW, Cibas ES, Brugge JS. A nonapoptotic cell death process, entosis, that occurs by cell-in-cell invasion. Cell. 2007 Nov 30;131(5):966-79.

Masciari S, Larsson N, Senz J, Boyd N, Kaurah P, Kandel MJ, Harris LN, Pinheiro HC, Troussard A, Miron P, Tung N, Oliveira C, Collins L, Schnitt S, Garber JE, Huntsman D. Germline E-cadherin mutations in familial lobular breast cancer. J Med Genet. 2007 Nov;44(11):726-31.

Shipitsin M, Campbell LL, Argani P, Weremowicz S, Bloushtain-Qimron N, Yao J, Nikolskaya T, Serebryiskaya T, Beroukhim R, Hu M, Halushka MK, Sukumar S, Parker LM, Anderson KS, Harris LN, Garber JE, Richardson AL, Schnitt SJ, Nikolsky Y, Gelman RS, Polyak K. Molecular definition of breast tumor heterogeneity. Cancer Cell. 2007 Mar;11(3):259-73.

Yang XH, Richardson AL, Torres-Arzayus MI, Zhou P, Sharma C, Kazarov AR, Andzelm MM, Strominger JL, Brown M, Hemler ME. CD151 accelerates breast cancer by regulating alpha 6 integrin function, signaling, and molecular organization. Cancer Res. 2008 May 1;68(9):3204-13.

Lu X, Lu X, Wang ZC, Iglehart JD, Zhang X, Richardson AL. Predicting features of breast cancer with gene expression patterns. Breast Cancer Res Treat. 2008 Mar;108(2):191-201.

Karnoub AE, Dash AB, Vo AP, Sullivan A, Brooks MW, Bell GW, Richardson AL, Polyak K, Tubo R, Weinberg RA. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature. 2007 Oct 4;449(7162):557-63.

Ince TA, Richardson AL, Bell GW, Saitoh M, Godar S, Karnoub AE, Iglehart JD, Weinberg RA. Transformation of different human breast epithelial cell types leads to distinct tumor phenotypes. Cancer Cell. 2007 Aug;12(2):160-70.

Boehm JS, Zhao JJ, Yao J, Kim SY, Firestein R, Dunn IF, Sjostrom SK, Garraway LA, Weremowicz S, Richardson AL, Greulich H, Stewart CJ, Mulvey LA, Shen RR, Ambrogio L, Hirozane-Kishikawa T, Hill DE, Vidal M, Meyerson M, Grenier JK, Hinkle G, Root DE, Roberts TM, Lander ES, Polyak K, Hahn WC. Integrative genomic approaches identify IKBKE as a breast cancer oncogene. Cell. 2007 Jun 15;129(6):1065-79.

Mani SA, Yang J, Brooks M, Schwaninger G, Zhou A, Miura N, Kutok JL, Hartwell K, Richardson AL, Weinberg RA. Mesenchyme Forkhead 1 (FOXC2) plays a key role in metastasis and is associated with aggressive basal-like breast cancers. Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):10069-74.

CLINICAL STUDIES

This Core facilitates all SPORE-related clinical research across the Dana-Farber Cancer Institute/Brigham and Women’s Hospital, Beth Israel Deaconess Medical Center, and Massachusetts General Hospital. These three institutions see over 4,000 new patients with breast cancer each year, and well over 15,000 patients are seen for ongoing therapy and/or follow-up visits. DF/HCC, a NCI-designated comprehensive cancer center, provides a linking structure for all three institutions. All investigators in the Breast SPORE conducting clinical trials or other research studies involving human subjects use the Clinical Studies Core. These studies include those specifically identified in SPORE projects, as well as studies supported by the NCI-Avon Progress for Patients program. The Core also provides support to selected non-SPORE DF/HCC investigators who are conducting trials that involve the acquisition of research biopsies. In addition, the Core identifies and obtains consent from patients for participation in our DF/HCC cohort studies, and research databases (Clinical Research Information System [CRIS] and Risk Evaluation and Cancer History [REACH]). The Core seeks to minimize delays in the activation of protocols, streamline patient recruitment, and consent studies across multiple institutions. The work of this Core assures that clinical studies in the SPORE are conducted expeditiously and with rigor, enhancing the likelihood that the clinical trials and their linked laboratory-based research will be successful.

COHORT STUDIES AND DATA BASES

Breast Cancer Cohort concentrates its efforts in three areas: (1) enrolling new patients for blood draws, banking of specimens, and clinical data collection; collecting clinical data for patients with banked specimens; and, responding to user requests for data. Our database now includes medical information for approximately 15,003 patients, and baseline survey data on an additional 9,094 patients seen for one-time consultations.

High Risk Cohort manages our Risk Evaluation and Cancer History (REACH) project. Only individuals at highest risk, who are evaluated in the Cancer Risk and Prevention Clinic in the Gillette Center of the Dana-Farber Cancer Institute, are eligible to participate. The Core collects questionnaire data from all clinical subjects. This includes family history and exposure data. Those with highest risk in specific categories are asked to provide 2-3 tubes of blood. These specific categories include strong family cancer history, early age at cancer diagnosis, family clustering of rare cancers with breast cancer, histologic lesions (ADH, LCIS) and therapeutic radiation to the chest (e.g., Hodgkin’s Disease survivors).

Databases maintained by the Core include a “high risk” application in the Clinical Research Information System (CRIS). Both cohorts use the CRIS-linked Specimen Tracking and Inventory Program (STIP) application, thus allowing us to better support translational research projects using fully annotated specimens. Pedigree data for the high-risk cohort is kept in a separate Progeny database that links family pedigrees with cancer risk modeling software and rigorously protects patient confidentiality.

Recent Publications:

Yen TW, Kuerer HM, Ottesen RA, Niland JC, Edge SG, Theriault RL, Weeks, JC. Impact of randomized clinical trial results on the use of tamoxifen following breast surgery for ductal carcinoma in situ in the National Comprehensive Cancer Network. J Clin Oncol 2007; 25: 3251-8

Desch CE, McNiff KK, Schneider EC, Schrag D, McClure J, Lepisto E, Donaldson MS, Kahn KL, Weeks JC, Ko CY, Stewart AK, Edge SB. The ASCO/NCCN quality measures. J Clin Oncol (in press).

Hassett MJ, Hughes ME, Niland JC, Ottesen R, Edge SB, Bookman MA, Carlson RW, Theriault RL, Weeks JC. Selecting high priority quality measures for breast cancer. Medical Care (in press).

Punglia RS, Hughes ME, Edge SB, Theriault RL, Bookman MA, Wilson JL, Ottesen RA, Niland JC, Weeks JC. Factors associated with guideline-concordance use of radiotherapy after mastectomy in the National Comprehensive Cancer Network. Int J Radiat Oncol Biol Phys (in press)

Wong Y, Ottesen R, Niland J, Hughes M, Theriault R, Edge S, Blayney D, Weeks JC. Continued use of trastuzumab beyond disease progression in the National Comprehensive Cancer Network Presentation at the American Society of Clinical Oncology annual meeting, June 2008.

Masciari S, Larsson N, Senz J, Boyd N, Kaurah P, Kandel MJ, Harris LN, Pinheiro HC, Troussard A, Miron P, Tung N, Oliveira C, Collins L, Schnitt S, Garber JE, Huntsman D. Germline E-cadherin mutations in familial lobular breast cancer. J Med Genet. 2007;44:726-31.

BIOSTATISTICS AND BIOINFORMATICS

This Core provides consultation and collaboration on quantitative methods plus analysis of high throughput genomic data to all SPORE investigators, projects, and cores. Biostatistical and bioinformatic expertise is available for the planning, conduct, analysis, and reporting of laboratory, animal, clinical, and epidemiological studies for SPORE projects. The Core consults with researchers for the evaluation of computer databases, publicly available statistical programs and genomic data, and data integration. In addition, the Core collaborates with researchers to develop statistical/bioinformatic programs to address specialized problems.

COMMUNICATIONS, PLANNING AND ADMINISTRATION (CPA)

This Core is charged with administrative oversight and performance management of the Projects, Cores, NCI-Avon Progress for Patients supplements, Career Development awards and Developmental Projects awards under this collaborative, multi-institutional translational grant. For administrative oversight, the Core relies heavily on the skilled and experienced staff in the Department of Cancer Biology at the Dana-Farber Cancer Institute (DFCI) to support the SPORE Director in the management of budgets and subcontracts. For best practices, the staff strictly adheres to generally accepted accounting principles that provide clear financial reporting and oversight. For performance management of the Projects and Cores, the SPORE Director relies on Advisory Committees to assist him in evaluating their progress. There are three advisory committees set up with defined roles: Breast Program/SPORE Steering Committee, External Advisory Board, and the Breast SPORE Director’s Leadership Counsel. In addition to the SPORE Director’s advisory groups, the Breast SPORE Core Coordinating Committee meets to review Core utilization and to discuss any issues that are of concern to the respective Cores. The Core provides vital integration of the SPORE with DF/HCC and the Program in Breast Cancer. Annually, the SPORE sponsors with the DF/HCC Program in Breast Cancer and DFCI Women’s Cancers Program, a symposium in breast cancer research.

The Core supports our Breast Cancer Advocacy Group. Currently, we have 15 active advocates in our group. Our Advocates regularly attend SPORE meetings, planning retreats, mini-Retreats, EAB retreats, and our annual breast cancer research symposium. Our Advocates are formally assigned to Projects and Cores with a researcher liaison available to assist in answering questions. Many of our Advocates have completed Project LEAD. Our Advocates have attended an annual course on “Breast Cancer: Current Controversies and New Horizons,” the annual ASCO Breast Cancer Symposium, and the annual San Antonio Breast Cancer Symposium.

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