Current Projects | Schuler Lab

Meet a critical member of the team, the NRL-PRL mouse:

In this transgenic mouse model, prolactin is expressed by mammary epithelia, mimicking the prolactin synthesis in breasts of women. This locally elevated concentration of prolactin ligand does not preselect target cells, enabling an unbiased investigation of outcomes. It also does not disturb estrous cycling, enabling study of the interactions of prolactin with ovarian steroids. Nulliparous females spontaneously develop aggressive metastatic ERα+ carcinomas, which model anti-estrogen resistant clinical breast cancers, and confirm the epidemiologic link between prolactin exposure and aggressive ERα+ cancer. This model permits examination of the dynamic in vivo processes that drive the development and progression of this subset of clinical cancers. Transplantation of these carcinomas and derived cell lines to syngeneic immunocompetent hosts enables examination of interactions with the microenvironment and treatment sensitivity.

References:

O’Leary, K.A., M.P. Shea, L.A. Schuler. Modeling prolactin actions in breast cancer in vivo: insights from the NRL-PRL mouse. Adv. Exp. Biol. Med. 846:201-220, 2015. PMCID: 4770878

O’Leary, K.A., M.P. Shea, S. Salituro, C.E. Blohm and L.A. Schuler. Prolactin alters the mammary epithelial hierarchy, increasing progenitors and facilitating ovarian steroid action. Stem Cell Reports 9:1167-1179, 2017. PMCID: 5639259

Campbell, K.M., K.A. O’Leary, D.E. Rugowski, W.A. Mulligan, E.K. Barnell, Z.L. Skidmore, K. Krysiak, M. Griffith, L.A. Schuler, O.L. Griffith. Spontaneous aggressive ERα mammary tumor model is driven by Kras activation, Cell Reports 28:1526-1537, 2019. Recognized by Mammary Cell News. PMCID:6713291

CURRENT PROJECTS

PROJECT 1: How does estrogen orchestrate the synergy among ER+ tumor cells, the extracellular matrix/ cancer associated fibroblasts, and macrophages/ inflammation, to fuel metastasis?

Estrogen acts on ER+ tumor cells and stromal cells in the microenvironment of the primary tumor to facilitate tumor progression.
–Mechanisms of metastasis
–Premetastatic conditioning
–Inflammatory mediators

Multiple cell types in the vicinity of ER+ breast cancers express different complements of estrogen receptors. We utilize the aggressive ER+ cancers that develop in the NRL-PRL model, in vitro systems, PDX models and clinical patient samples to illuminate the role of estrogen in dissemination and pulmonary metastatic colonization, with implications for therapeutic responses, dormancy and recurrence of ER+ breast cancer, and reveal potential strategies for intervention.

Current research in our lab aims to:

Identify the steps in metastatic progression of ER+ breast cancer which are altered by estrogen activity in ER+ tumor cells as well as other estrogen target cells.
Determine how estrogen action on CAFs modifies the stromal ECM to mediate tumor progression, determine the receptors that mediate this action, and identify ECM signatures from ER+ invasive ductal carcinoma biopsy tissues that instruct estrogen action on tumor cells.
Determine how estrogen impacts immune metastatic mediators, including macrophage activity and the inflammatory tumor microenvironment.
Evaluate the ability of standard of care therapeutic approaches to reverse E2-promoted steps in metastasis and post-treatment estrogen re-exposure to promote growth of residual pulmonary lesions, and interrogate the interrelationships among E2-altered ECM structure, and macrophage activity/inflammation.

References:

Barcus C.E., K.A. O’Leary, J.L. Brockman, D.E. Rugowski, Y. Liu, N. Garcia, M. Yu, P.J. Keely, K.W. Eliceiri, L.A. Schuler. Elevated collagen-I augments tumor progressive signals, intravasation and metastasis of prolactin-induced estrogen receptor alpha positive mammary tumor cells. Breast Cancer Res 19:1-13, 2017. PMCID: 5244528.

Shea, M.P., K.A. O’Leary, S.A. Fakhraldeen, V. Goffin, A. Friedl, K.B. Wisinski, C.M. Alexander and L.A. Schuler. Anti-estrogen therapy increases plasticity and cancer stemness of prolactin-induced ERα+ mammary carcinomas. Cancer Res. 78:1672-1684, 2018. PMCID: 5882549.

Jallow, F., K.A. O’Leary, D.E. Rugowski, J.E. Guerrero, S.M. Ponik, and L.A. Schuler. Bidirectional interactions between the extracellular matrix and estrogen and antagonists, driving breast cancer progression, Oncogene 38: 6913-6915, 2019. Recognized by Extracellular Matrix News and Mammary Cell News; featured as Matrix Biology Highlight 87:8-9, 2020. PMCID: 6814534

PROJECT 2: How can we improve the efficacy of immunotherapies to treat advanced ER+ disease?

Like clinical ER+ breast cancers, ER+ tumors that develop in NRL-PRL mice show: i. low infiltration of CD8+ cytotoxic T cells (inset, thymus), but ii. higher numbers of immunosuppressive F4/80+ macrophages.

Immunotherapies offer the exciting potential of durable disease treatment, even for metastatic disease. However, application to ER+ breast cancer has been disappointing. In general, these tumors express few neo-antigens, and contain few infiltrating lymphocytes but high numbers of immunosuppressive cell subpopulations, indicators of immunologically “cold” cancers. The communication networks by which aggressive ER+ cancers orchestrate their suppressive immune microenvironment, how this differs between the metastatic niche and the primary tumor microenvironment is not well understood.

Current research in our lab aims to:

Spatially and functionally profile the immune microenvironments of primary ER+ tumors and pulmonary metastases
Determine how standard of care treatments (anti-estrogens, mTOR inhibitors, immune checkpoint blockade) on the environment of lung metastases
Suggest potential targetable pathways, which can be tested in future experiments

PROJECT 3: How does prolactin contribute to the development of ERα+ breast cancer?

Schematic of the effects of prolactin on transcriptional/ paracrine regulators, resulting in augmented progenitor/stem cells and perturbed differentiation pathways, which may contribute to heightened risk for breast cancer. The conceptualized mammary epithelial hierarchy in normal wildtype mice (left) is regulated by multiple transcription factors and paracrine signals. Locally elevated prolactin in NRL-PRL females (right) alters the levels of many of these mRNAs. Transcripts elevated above wildtype levels are shown in larger, red font; reduced transcripts are shown in smaller, green font. (From O’Leary et al., Stem Cell Reports, in press).

Strong epidemiologic evidence links elevated levels of circulating prolactin to increased risk for aggressive ERα+ breast cancer, which accounts for the majority of breast cancer mortality (Tworoger et al., Cancer Research, 2013; Tikk, et al., Annals of Oncology, 2014).

Current research in our lab aims to:

Understand the effects of prolactin and crosstalk with ovarian steroids on mammary epithelial dynamics, progenitor/ stem cells, and transcriptional programs that regulate epithelial differentiation
Elucidate the effects of prolactin and crosstalk with estrogen and progesterone on the mammary microenvironment, including structure of the extracellular matrix and immune populations
Illuminate the crosstalk of prolactin signals with other mammary oncogenes, to understand how prolactin influences tumorigenesis in different contexts, and modulates the phenotype and therapeutic sensitivity of the resulting cancers.

References:

O’Leary, K.A., D.E. Rugowski, M.P. Shea, R. Sullivan, A.R. Moser and L.A. Schuler. Prolactin synergizes with canonical Wnt signals to drive development of ER+ cancers via activation of the Notch pathway. Cancer Lett 503:231-239, 2021.