Program Official

Principal Investigator

Anna Tate
Riegel
Awardee Organization

Georgetown University
United States

Fiscal Year
2020
Activity Code
R01
Early Stage Investigator Grants (ESI)
Not Applicable
Project End Date

(PQ6) Molecular Mechanisms Driving Benign to Malignant Transitions in Breast Cancer

Ductal carcinoma in situ (DCIS) of the breast is a frequently-diagnosed, heterogeneous, pre-neoplastic lesion that can give rise to invasive and metastatic breast cancer (BC). Based on outcome data it is predicted that the majority of DCIS cases would not progress to invasive disease. A better understanding of the mechanism that drive hyperplasia and DCIS disease progression could offer potential targets for prevention of pre-neoplastic development and progression and perhaps reduce over-treatment of benign disease. However, the genetic and signaling changes that can drive invasion and metastasis that occur in a sub-population of DCIS cells, remain undefined. We plan to pursue this gap in knowledge based on our recent findings. We will focus on the tumor suppressor ANCO1 (=ANKRD11) that binds to and regulates the coactivator oncogene, Amplified in Breast cancer 1 (AIB1) that is overexpressed in DCIS. Reduction of AIB1 causes a loss of DCIS bipotential progenitor breast cancer initiating cells (BCIC) and prevents DCIS progression to invasive disease in vivo. AIB1-∆4, is a naturally occurring, more active isoform of AIB1 that lacks the N-terminal domain can drive early stage hyperplasia and DCIS in the mammary gland of transgenic mice. The increased oncogenic potential of AIB1-∆4 is in part due to its lack of repression by ANCO1. Loss of ANCO1 or the gain of ∆4 expression in breast cancer cells leads to changes in recruitment of HDACs and methylated histones to transcription factor complexes and increases transcription of genes that could drive pre-neoplasia. Here we will examine the hypothesis that epigenetic alterations driven by the loss of ANCO1 and/or the gain of AIB1- Δ4 expression results in gene expression changes in pre-neoplastic cells that drive transit to invasive cancer. The aims are: Specific Aim 1: Determine the relative roles of ANCO1, AIB1-FL and -∆4 during development and progression of pre-neoplasia in human breast epithelia Specific Aim 2: Determine genomic regions where ANCO1, AIB1-FL and -∆4 bind and directly modify the epigenome during pre-neoplastic development and progression of breast cancer Specific Aim 3: Determine if alterations in the relative levels of ANC01, AIB1-FL or -∆4 impact the development of pre-neoplasia and progression to invasive cancer in syngeneic mouse models.

Publications

  • Saenz FR, Ory V, Schmidt MO, Kallakury BV, Mueller SC, Furth PA, Wellstein A, Riegel AT. Depletion of the Transcriptional Coactivator Amplified in Breast Cancer 1 (AIB1) Uncovers Functionally Distinct Subpopulations in Triple-Negative Breast Cancer. Neoplasia (New York, N.Y.). 2019 Oct;21(10):963-973. Epub 2019 Aug 19. PMID: 31437536
  • Miller J, Dakic A, Spurgeon M, Saenz F, Kallakury B, Zhao B, Zhang J, Zhu J, Ma Q, Xu Y, Lambert P, Schlegel R, Riegel AT, Liu X. AIB1 is a novel target of the high-risk HPV E6 protein and a biomarker of cervical cancer progression. Journal of medical virology. 2022 Aug;94(8):3962-3977. Epub 2022 Apr 27. PMID: 35437795
  • Ory V, Kietzman WB, Boeckelman J, Kallakury BV, Wellstein A, Furth PA, Riegel AT. The PPARγ agonist efatutazone delays invasive progression and induces differentiation of ductal carcinoma in situ. Breast cancer research and treatment. 2018 May;169(1):47-57. Epub 2018 Jan 19. PMID: 29350308
  • Yuan M, Barefoot ME, Peterson K, Campbell MJ, Blancato JK, Chen M, Schmidt MO, Kiliti AJ, Fang HB, Wellstein A, Riegel AT, Sharif GM. Loss of ANCO1 Expression Regulates Chromatin Accessibility and Drives Progression of Early-Stage Triple-Negative Breast Cancer. International journal of molecular sciences. 2023 Jul 15;24. (14). PMID: 37511268
  • Sharif GM, Der L, Riegel AT, Paranjape M, Wellstein A. Real-Time Detection and Capture of Invasive Cell Subpopulations from Co-Cultures. Journal of visualized experiments : JoVE. 2022 Mar 30;(181). PMID: 35435909
  • Lin YN, Nasir A, Camacho S, Berry DL, Schmidt MO, Pearson GW, Riegel AT, Wellstein A. Monitoring Cancer Cell Invasion and T-Cell Cytotoxicity in 3D Culture. Journal of visualized experiments : JoVE. 2020 Jun 23;(160). PMID: 32658183
  • Kushner MH, Ory V, Graham GT, Sharif GM, Kietzman WB, Thevissen S, Yuan M, Schmidt MO, Wellstein A, Riegel AT. Loss of ANCO1 repression at AIB1/YAP targets drives breast cancer progression. EMBO reports. 2020 Jan 7;21(1):e48741. Epub 2019 Dec 2. PMID: 31788936
  • Westcott JM, Camacho S, Nasir A, Huysman ME, Rahhal R, Dang TT, Riegel AT, Brekken RA, Pearson GW. ΔNp63-Regulated Epithelial-to-Mesenchymal Transition State Heterogeneity Confers a Leader-Follower Relationship That Drives Collective Invasion. Cancer research. 2020 Sep 15;80(18):3933-3944. Epub 2020 Jul 13. PMID: 32661136
  • Lin YN, Schmidt MO, Sharif GM, Vietsch EE, Kiliti AJ, Barefoot ME, Riegel AT, Wellstein A. Impaired CXCL12 signaling contributes to resistance of pancreatic cancer subpopulations to T cell-mediated cytotoxicity. Oncoimmunology. 2022 Feb 3;11(1):2027136. doi: 10.1080/2162402X.2022.2027136. eCollection 2022. PMID: 35127250
  • Kiliti AJ, Sharif GM, Martin MB, Wellstein A, Riegel AT. AIB1/SRC-3/NCOA3 function in estrogen receptor alpha positive breast cancer. Frontiers in endocrinology. 2023 Aug 30;14:1250218. doi: 10.3389/fendo.2023.1250218. eCollection 2023. PMID: 37711895
  • Sharif GM, Campbell MJ, Nasir A, Sengupta S, Graham GT, Kushner MH, Kietzman WB, Schmidt MO, Pearson GW, Loudig O, Fineberg S, Wellstein A, Riegel AT. An AIB1 Isoform Alters Enhancer Access and Enables Progression of Early-Stage Triple-Negative Breast Cancer. Cancer research. 2021 Aug 15;81(16):4230-4241. Epub 2021 Jun 16. PMID: 34135000
  • Gallanis GT, Sharif GM, Schmidt MO, Friedland BN, Battina R, Rahhal R, Davis JE Jr, Khan IS, Wellstein A, Riegel AT. Stromal Senescence following Treatment with the CDK4/6 Inhibitor Palbociclib Alters the Lung Metastatic Niche and Increases Metastasis of Drug-Resistant Mammary Cancer Cells. Cancers. 2023 Mar 22;15. (6). PMID: 36980794
  • Gallanis GT, Pericas RI, Riegel AT, Pohlmann PR. An evaluation of palbociclib as a breast cancer treatment option: a current update. Expert opinion on pharmacotherapy. 2021 Feb;22(3):281-290. Epub 2020 Nov 16. PMID: 33198527
  • Kietzman WB, Graham GT, Ory V, Sharif GM, Kushner MH, Gallanis GT, Kallakury B, Wellstein A, Riegel AT. Short- and Long-Term Effects of CDK4/6 Inhibition on Early-Stage Breast Cancer. Molecular cancer therapeutics. 2019 Dec;18(12):2220-2232. Epub 2019 Aug 26. PMID: 31451564