Abstract 1174: PROCR+/ZEB1+/PDGFRalpha+ (PZP) multipotent cells of the breast as potential biologic mediators of breast cancer disparity
Authors: Harikrishna Nakshatri, Brijesh Kumar, Poornima Bhat-Nakshatri
Journal: Cancer Research (2020)

Abstract African American (AA) women suffer higher mortality from the aggressive breast cancer subtype, triple negative breast cancer (TNBC), than Caucasian (CA) women. Furthermore, basal-like and mesenchymal-like TNBCs with elevated intra-tumor heterogeneity are significantly more common in AA women. In addition, breast cancer recurrence after ductal carcinoma in situ (DCIS) diagnosis and eventual breast cancer related deaths are higher in AA women. Whether worse outcome in AA women is due to an increased incidence of TNBC or unique biological factors that promote aggressive biology is an important but unresolved challenge in cancer disparities research. We recently reported enrichment of a unique population of cells that express stemness-associated PROCR and ZEB1 in the normal breasts of AA women compared to CA women. These cells increased in the cancerous breasts of CA women suggesting their role in breast cancer progression. We found these cells express PDGFRα, similar to adipogenic progenitors of the mouse mammary gland that transition into epithelial cells during lobulo-alveologenesis. These cells, renamed as PZP cells (PROCR+, ZEB1+, PDGFRα+), trans-differentiated into EpCAM+ epithelial cells upon transformation by HRasG12V ± SV40 T-antigen suggesting that breast tumors in AA women can originate from two cell sources- PZP cells and luminal epithelial cells. Transformed PZP cells generated pleomorphic anaplastic sarcomas, which comprise of 0.5-1% of all breast neoplasms. Under adipogenic growth conditions, PZP cells transdifferentiated into adipocytes indicating their ability to alter the tumor microenvironment. To obtain potential insight into signaling pathway alterations in epithelial and PZP cells as a consequence of their cross-talk, we performed cytokine/chemokine profiling of factors secreted by an immortalized luminal epithelial cell line, a PZP cell line and both co-cultured together (50% of each cell line) for ~12 hours. While luminal epithelial cell line expressed several ligands such as PDGF-AA and osteopontin, which can affect trans-differentiation of PZP cells, PZP cells expressed factors such as EGF, HGF and SDF-1α, which can signal in luminal cells. Interestingly, IL-6 is produced only under co-culture condition suggesting that PZP-epithelial cell cross-talk can create pro-inflammatory, invasive, and metastatic conditions in the breast microenvironment. Because the normal breasts of AA women naturally contain higher number of PZP cells, PZP-breast tumor cell interaction could occur early during tumor evolution in AA compared to CA women, which creates conditions conducive for early metastatic dissemination in AA women. These genetic ancestry-dependent differences in pro-inflammatory, invasive, and pro-metastatic status of the breast could explain for disparity in breast cancer outcomes. Citation Format: Harikrishna Nakshatri, Brijesh Kumar, Poornima Bhat-Nakshatri. PROCR+/ZEB1+/PDGFRalpha+ (PZP) multipotent cells of the breast as potential biologic mediators of breast cancer disparity [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1174.