Author ORCID Identifier

0000-0002-5768-2378

Date of Graduation

12-2022

Document Type

Dissertation (PhD)

Program Affiliation

Cancer Biology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Wendy Woodward

Committee Member

Bisrat Debeb

Committee Member

David Piwnica-Worms

Committee Member

George Eisenhoffer

Committee Member

Melissa Aldrich

Abstract

Inflammatory breast cancer (IBC) is a rapidly progressing, rare and highly lethal form of breast cancer. IBC is a clinical diagnosis, requiring >1/3 involvement on the affected breast and/or skin by erythema, and disease onset of < 6 months. The clinical symptoms of IBC vary in severity and presentation, these include redness, warmth, skin thickening and bruised or pink/purple discoloration appearance and skin changes such as peau d’orange. These skin symptoms are not attributed to inflammation, rather IBC is characterized by florid lymphovascular tumor emboli clogging dermal lymphatics. This leads to “classic” symptoms of breast swelling and skin edema or discoloration. To date, unique genomic drivers which differentiate IBC from non-IBC invasive breast cancers have not been identified highlighting a role for the microenvironment. Several epidemiological studies have unveiled subtype-specific risk factors associated with IBC that are known to alter the microenvironment. Obesity is an established risk factor for all subtypes of IBC. Never-breastfeeding increases risk for developing the most aggressive, triple-negative IBC. Further, never breastfeeding is associated with later clinical stage and worse outcomes. We worked to model these overlapping risk factors to understand microenvironment changes that may lead to the lymphatic change’s indicative of IBC.

First, we investigated the association of a “classic” triad of clinical IBC signs with overall survival among patients to demonstrate the most overt clinical findings of lymphatic involvement were impacting prognosis. We evaluated a triad of IBC signs, including swollen involved breast, nipple change, and diffuse skin change, using breast medical photographs from patients enrolled on a prospective IBC registry. We reported that the ten-year OS was 29.7% among patients with the classic sign triad versus 57.2% for non-classic (P < .0001). We determined that a triad of classic IBC signs independently predicted OS in patients diagnosed with IBC suggesting the clinical outcome of diffuse lymphatic invasion by IBC is prognostic, and potentially that targeting the mechanisms that promote lymphatic function and tumor invasion may improve outcomes.

Our prior work implied the changes in the breast that permit florid lymphatic involvement may even occur prior to tumor initiation. Noting a limitation of existing studies of breast cancer risk factors is the experimental isolation of risk factors, which fails to model the patient experience. Thus, we modeled synergistic effects of IBC risk factors, obesity and weaning timing, on in vivo lymphatic function pre- and post-tumor initiation, IBC tumor growth, and the mammary gland microenvironment. We hypothesized that weaning status (duration of breast feeding) and high fat diet (HFD) would synergize to induce pro-lymphatic changes in the microenvironment before tumor initiation and promote IBC tumor growth. We found that HFD increased lymphatic contractile activity prior to tumor initiation. This HFD-induced increase in lymphatic function correlated to increased SUM149 tumor growth and increased inflammatory cells in the mammary gland. Tumors increased lymphatic function to a similar extent. Increased CCL21+ cells, a ligand for lymphatic traffic homing, was correlated to pulsing. Thus, the relationship between lymphatic pulsing, tumor growth and CCR7-CCL21 related tumor trafficking warrant further investigation.

CCR7 is an immune cell receptor that mediates immune cell trafficking into lymphatics that can be expressed on tumor cells. We examined the expression of CCR7 in IBC and non-IBC cell lines, and IBC patient tumors to determine the prevalence of this receptor in IBC tumor cells. We found that CCR7 gene expression is increased in IBC versus non-IBC tumors, and was present across tumor subtypes in IBC cell lines and in both ER+ and ER- IBC patient tumors. Further, CCR7 was expressed on 23/24 IBC patient samples assessed by immunohistochemistry. This highlights the potential direction for developing novel therapies targeting CCR7, to improve therapeutic options and outcomes for IBC patients.

Keywords

IBC, inflammatory breast cancer, High fat diet, lymphatic pulsing, podoplanin, mammary gland, weaning, breastfeeding, pregnancy, microenvironment, CCR7, CCL21, IBA-1, CD163, PoEM, presentation

Available for download on Saturday, December 09, 2023

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