ILC Program of Excellence – Awards, Publications, & Grants
Our research program, led by Steffi Oesterreich and Adrian V. Lee at the University of Pittsburgh and UPMC Hillman Cancer Center, focuses on understanding the unique biology of invasive lobular carcinoma (ILC) and translating these insights into improved diagnostics and therapies. We integrate molecular, genomic, and clinical studies through extensive collaborations with national and international partners to advance precision medicine for patients with ILC.
1. Estrogen Receptor Biology and Endocrine Resistance
Our research has long focused on how estrogen receptor (ER) signaling drives lobular breast cancer biology and contributes to endocrine therapy response and resistance. We have characterized unique ER-mediated gene expression patterns in ILC, uncovered the role of WNT4 and lipid metabolism in resistance, and identified mechanisms such as ESR1 fusions and NF1 loss that underlie acquired resistance. Together, these studies define the molecular diversity of ER function and reveal novel therapeutic vulnerabilities in endocrine-resistant ILC.
Sikora MJ, et al. (2014). “Invasive lobular carcinoma cell lines are characterized by unique estrogen-mediated gene expression patterns and altered tamoxifen response.” Cancer Res 74(5): 1463–1474. DOI: 10.1158/0008-5472.CAN-13-2830
Sikora MJ, et al. (2016). “WNT4 mediates estrogen receptor signaling and endocrine resistance in invasive lobular carcinoma cell lines.” Breast Cancer Res 18(1): 92. DOI: 10.1186/s13058-016-0743-4
Du T, et al. (2018). “Key regulators of lipid metabolism drive endocrine resistance in invasive lobular breast cancer.” Breast Cancer Res 20(1): 106. DOI: 10.1186/s13058-018-1039-0
Bossart EA, et al. (2019). “SNAIL is induced by tamoxifen and leads to growth inhibition in invasive lobular breast carcinoma.” Breast Cancer Res Treat 175(2): 327–337. DOI: 10.1007/s10549-019-05148-1
Sreekumar S, et al. (2020). “Differential Regulation and Targeting of Estrogen Receptor alpha Turnover in Invasive Lobular Breast Carcinoma.” Endocrinology 161(9). DOI: 10.1210/endocr/bqaa087
Shackleford MT, et al. (2020). “Estrogen Regulation of mTOR Signaling and Mitochondrial Function in Invasive Lobular Carcinoma Cell Lines Requires WNT4.” Cancers (Basel) 12(10). DOI: 10.3390/cancers12103010
Yates ME, et al. (2024). “ESR1 Fusions Invoke Breast Cancer Subtype-Dependent Enrichment of Ligand-Independent Oncogenic Signatures and Phenotypes.” Endocrinology 165(10). DOI: 10.1210/endocr/bqae092
Sokol ES, et al. (2019). “Loss of function of NF1 is a mechanism of acquired resistance to endocrine therapy in lobular breast cancer.” Ann Oncol 30(1): 115–123. DOI: 10.1093/annonc/mdy474
Sottnik JL, et al. (2024). “WNT4 Regulates Cellular Metabolism via Intracellular Activity at the Mitochondria in Breast and Gynecologic Cancers.” Cancer Res Commun 4(1): 134–151. DOI: 10.1158/2767-9764.CRC-23-0170
2. E-Cadherin Loss, IGF1R Signaling, and Collateral Pathways
A hallmark of invasive lobular carcinoma is loss of E-cadherin (CDH1), which disrupts cell adhesion and profoundly alters cell signaling. Our team has shown that E-cadherin loss activates the IGF1R pathway, creating therapeutic opportunities, and that some ILCs without CDH1 mutations rely on alternative genomic or epigenomic mechanisms. We have also discovered cAMP/PKA/CREB pathway enrichment, underscoring how E-cadherin loss drives distinctive molecular rewiring in ILC.
Nagle AM, et al. (2018). “Loss of E-cadherin Enhances IGF1-IGF1R Pathway Activation and Sensitizes Breast Cancers to Anti-IGF1R/InsR Inhibitors.” Clin Cancer Res 24(20): 5165–5177. DOI: 10.1158/1078-0432.CCR-18-0364
Elangovan A, et al. (2022). “Loss of E-cadherin Induces IGF1R Activation and Reveals a Targetable Pathway in Invasive Lobular Breast Carcinoma.” Mol Cancer Res 20(9): 1405–1419. DOI: 10.1158/1541-7786.MCR-21-0993
Dopeso H, et al. (2024). “Genomic and epigenomic basis of breast invasive lobular carcinomas lacking CDH1 genetic alterations.” NPJ Precis Oncol 8(1): 33. DOI: 10.1038/s41698-024-00594-z
Logan GJ, et al. (2015). “Molecular drivers of lobular carcinoma in situ.” Breast Cancer Res 17: 76. DOI: 10.1186/s13058-015-0580-5
Puthanmadhom Narayanan S, et al. (2024). “Transcriptomic analysis identifies enrichment of cAMP/PKA/CREB signaling in invasive lobular breast cancer.” Breast Cancer Res 26(1): 149. DOI: 10.1186/s13058-024-01847-3
3. Genomics, Transcriptomics, and Molecular Subtypes
Our integrative genomic and transcriptomic analyses have revealed the molecular diversity of ILC, distinguishing it from ductal carcinoma. We identified recurrent ESR1 and FGFR4 amplifications, characterized single-cell transcriptional heterogeneity, and contributed to spatial and computational studies of mixed and lobular-like tumors. This work continues to define ILC as a distinct and heterogeneous molecular disease.
Ciriello G, et al. (2015). “Comprehensive Molecular Portraits of Invasive Lobular Breast Cancer.” Cell 163(2): 506–519. DOI: 10.1016/j.cell.2015.09.033
Cao L, et al. (2019). “Frequent amplifications of ESR1, ERBB2 and MDM4 in primary invasive lobular breast carcinoma.” Cancer Lett 461: 21–30. DOI: 10.1016/j.canlet.2019.07.020
Levine KM, et al. (2019). “FGFR4 overexpression and hotspot mutations in metastatic ER+ breast cancer are enriched in the lobular subtype.” NPJ Breast Cancer 5: 19. DOI: 10.1038/s41523-019-0100-4
Chen F, et al. (2021). “Single-Cell Transcriptomic Heterogeneity in Invasive Ductal and Lobular Breast Cancer Cells.” Cancer Res 81(2): 268–281. DOI: 10.1158/0008-5472.CAN-20-2392
Shah OS, et al. (2024). “Spatial molecular profiling of mixed invasive ductal and lobular breast cancers reveals heterogeneity in intrinsic molecular subtypes, oncogenic signatures, and mutations.” Proc Natl Acad Sci U S A 121(31): e2322068121. DOI: 10.1073/pnas.2322068121
Yu J, et al. (2023). “Clinicopathologic and genomic features of lobular like invasive mammary carcinoma: is it a distinct entity?” NPJ Breast Cancer 9(1): 60. DOI: 10.1038/s41523-023-00617-z
Kurozumi S, et al. (2020). “Targetable ERBB2 mutation status is an independent marker of adverse prognosis in invasive lobular carcinoma.” Breast Cancer Res 22(1): 85. DOI: 10.1186/s13058-020-01293-0
4. Tumor Microenvironment and Immune Landscape
We have found that ILC tumors exhibit a distinctive immune microenvironment compared to ductal cancers, often enriched for macrophages and unique immune-evasive mechanisms. By linking transcriptomic subtypes to immune infiltration, our work suggests new avenues for immunotherapy and highlights the complexity of immune biology in ER+ breast cancers.
Oesterreich S, et al. (2018). “Opening the Door for Immune Oncology Studies in Invasive Lobular Breast Cancer.” J Natl Cancer Inst 110(7): 696–698. DOI: 10.1093/jnci/djy041
Du T, et al. (2018). “Invasive lobular and ductal breast carcinoma differ in immune response, protein translation efficiency and metabolism.” Sci Rep 8(1): 7205. DOI: 10.1038/s41598-018-25672-3
Onkar S, et al. (2023). “Immune landscape in invasive ductal and lobular breast cancer reveals a divergent macrophage-driven microenvironment.” Nat Cancer 4(4): 516–534. DOI: 10.1038/s43018-023-00594-9
Onkar SS, et al. (2023). “The Great Immune Escape: Understanding the Divergent Immune Response in Breast Cancer Subtypes.” Cancer Discov 13(1): 23–40. DOI: 10.1158/2159-8290.CD-22-0812
Chen F, et al. (2024). “Immune Infiltration Correlates with Transcriptomic Subtypes in Primary ER+ Invasive Lobular Breast Cancer.” NPJ Precis Oncol 8(1): 257. DOI: 10.1038/s41698-024-00601-3
5. Clinical, Pathologic, and Translational Studies
Our collaborators and team have sought to define the unique clinical behavior of ILC—its metastatic patterns, diagnostic challenges, and response to therapy. Through large collaborative efforts, we have shaped international understanding of ILC’s presentation, outcomes, and clinical management, bridging molecular discoveries with patient impact.
Mathew A, et al. (2017). “Distinct Pattern of Metastases in Patients with Invasive Lobular Carcinoma of the Breast.” Geburtshilfe Frauenheilkd 77(6): 660–666. DOI: 10.1055/s-0043-107785
Carleton N, et al. (2022). “Is the Choosing Wisely Recommendation for Omission of Sentinel Lymph Node Biopsy Applicable for Invasive Lobular Carcinoma?” Ann Surg Oncol 29(9): 5379–5382. DOI: 10.1245/s10434-022-11885-7
Oesterreich S, et al. (2022). “Clinicopathological Features and Outcomes Comparing Patients With Invasive Ductal and Lobular Breast Cancer.” J Natl Cancer Inst 114(11): 1511–1522. DOI: 10.1093/jnci/djac104
Foldi J, et al. (2025). “Long-term outcomes by lobular vs ductal histology in 4 National Surgical Adjuvant Breast and Bowel Project adjuvant breast cancer trials.” J Natl Cancer Inst 117(1): 163–168. DOI: 10.1093/jnci/djae067
De Schepper M, et al. (2022). “Results of a worldwide survey on the currently used histopathological diagnostic criteria for invasive lobular breast cancer.” Mod Pathol 35(12): 1812–1820. DOI: 10.1038/s41379-022-01066-4
Nunes R, et al. (2021). “Prognostic Utility of Breast Cancer Index to Stratify Distant Recurrence Risk in ILC.” Clin Cancer Res 27(20): 5688–5696. DOI: 10.1158/1078-0432.CCR-21-0698
Nasrazadani A, et al. (2023). “Mixed invasive ductal lobular carcinoma is clinically and pathologically more similar to invasive lobular than ductal carcinoma.” Br J Cancer 128(6): 1030–1039. DOI: 10.1038/s41416-022-02119-2
Van Baelen K, et al. (2025). “Clinical challenges and proposed solutions for patients with invasive lobular breast cancer.” Ann Oncol. DOI: 10.1016/j.annonc.2025.02.004
6. Model Development, Bioinformatics, and Collaborative Infrastructure
Our group and collaborators have developed and characterized a wide array of ILC models, including cell lines, organoids, and patient-derived xenografts (PDXs), to better study lobular biology and therapeutic response. Through integrated bioinformatics and systems approaches, we have created publicly available resources that support collaborative discovery and reproducible science across the field.
Tasdemir N, et al. (2018). “Comprehensive Phenotypic Characterization of Human Invasive Lobular Carcinoma Cell Lines in 2D and 3D Cultures.” Cancer Res 78(21): 6209–6222. DOI: 10.1158/0008-5472.CAN-18-1613
Tasdemir N, et al. (2020). “Proteomic and transcriptomic profiling identifies mediators of anchorage-independent growth and roles of inhibitor of differentiation proteins in invasive lobular carcinoma.” Sci Rep 10(1): 11487. DOI: 10.1038/s41598-020-68129-3
Ma T, et al. (2017). “A Joint Bayesian Model for Integrating Microarray and RNA Sequencing Transcriptomic Data.” J Comput Biol 24(7): 647–662. DOI: 10.1089/cmb.2017.0034
Shah OS, et al. (2023). “Multi-omic characterization of invasive lobular carcinoma cell lines defines the Invasive Lobular Carcinoma Cell Line Encyclopedia (ICLE).” bioRxiv. DOI: 10.1101/2023.04.05.535672
Sflomos G, et al. (2021). “Atlas of Lobular Breast Cancer Models: Challenges and Strategic Directions.” Cancers (Basel) 13(21). DOI: 10.3390/cancers13215150
Elangovan A, et al. (2023). “Characterization of WCRC-25, a novel luminal invasive lobular breast cancer cell line.” bioRxiv. DOI: 10.1101/2023.09.21.558678
Hooda J, et al. (2025). “Molecular credentialing of invasive lobular carcinoma PDX models.” bioRxiv. DOI: 10.1101/2025.02.12.599812
7. Advocacy, Collaboration, and Global Research Networks
Our research has always been strengthened by close collaboration with patient advocates and international research networks. Together, we have worked to identify shared research priorities, harmonize diagnostic standards, and accelerate discovery through global partnerships.
Pate L, et al. (2021). “How Researchers, Clinicians and Patient Advocates Can Accelerate Lobular Breast Cancer Research.” Cancers (Basel) 13(13). DOI: 10.3390/cancers13133194
Oesterreich S, et al. (2024). “International survey on invasive lobular breast cancer identifies priority research questions.” NPJ Breast Cancer 10(1): 61. DOI: 10.1038/s41523-024-00631-1
