Linda A. Schuler, VMD, PHD

Pubmed

More information:

• Schuler Laboratory Home Page

Research Description:

The physiologic growth, differentiation and functional activity of the breast are orchestrated by a network of hormones, growth factors, and developmental regulators. Not surprisingly, many of these factors are implicated in the development and progression of breast cancer. Understanding this interplay can lead to effective therapeutic approaches with minimal side effects, as well as potential preventative strategies.

Prolactin is a principle regulator of mammary function. Epidemiologic studies support its importance in the “luminal” subtype of breast cancer. Elevated prolactin is associated with a higher risk for this cancer, established tumors express higher levels of prolactin receptors than adjacent normal tissue, and prolactin activity is associated with disease progression and resistance to endocrine and conventional chemotherapies.

We have developed unique models to understand the underlying mechanisms. Our transgenic mouse model, NRL-PRL, enables us to examine effects on mammary stem and progenitor cells as well as cancer stem cells, and crosstalk with other oncogenic factors in the dynamic in vivo context. Our cell culture models facilitate molecular dissection of signaling pathways, cell context, including extracellular matrix, and mechanisms of interactions with other hormones and growth factors, including receptor trafficking.

These studies have implications not only for carcinogenic processes in breast cancer, but also for prostatic cancer, which shares many underlying processes.

Selected References:

• Barcus C.E., P.J. Keely, K.W. Eliceiri, L.A. Schuler.  Prolactin signals through focal adhesion complexes are increased by a stiff extracellular matrix environment in breast cancer cells, Oncotarget 7: 48093-48106, 2016.
• 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.
• 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.
• 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.
• 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, 38:6913-6925, 2019.
• Schuler, L.A. F.E. Murdoch. Endogenous and Therapeutic Estrogens: Maestro conductors of the microenvironment of ER+ breast cancers. Cancers 13: 3725, 2021. https://doi.org/10.3390/cancers13153725
• Schuler, L.A. and K.A. O’Leary. Prolactin:  the third hormone in breast cancer. Front Endocrinol 13:910978 DOI: 10.3389/fendo.2022.910978, 2022.