Circulating CAFs (cCAFs) Enable Phospho-PR-Driven Stemness Programs in cCAF/Tumor Cell Clusters Required for Luminal Breast Cancer Recurrence
Abstract
Breast cancer death is from disease metastasis. While Luminal (estrogen receptor+/progesterone receptor+) breast cancer (BC) has a better prognosis compared to triple-negative/basal-like BC, up to 40% of women with luminal BC ultimately fail on ERalpha (ER) or estrogen-blocking therapies and recur with metastatic disease. Furthermore, late recurrence 10 or more years post-treatment is an increasingly appreciated life-threatening problem with this overall good prognosis BC subtype. The majority of tamoxifen-resistant BCs retain some level of steroid hormone receptor (SR) expression -- it is the aberrant action of these SRs, often in collaboration with local growth factors, that now controls these BCs. Research has largely centered on ER “escape” from therapy. But in fact, there is great potential in targeting progesterone receptors (PRs) as important effectors of ERs that can affect hormone responsiveness and drive cancer stem/progenitor cell biology (referred to as “stemness” herein) and tumor expansion. Proliferation vs. stem cell “self-renewal” are separate processes that often oppose each other such that targeting primary tumor growth with tamoxifen can enhance or select for stemness. Most recently, PRs were implicated in early disseminating metastatic mouse BC cells, but the mechanisms remain undefined. BC metastasis results from cancer cells escaping the primary tumor site and surviving in circulation to seed distant organ sites. Their presence in circulation (CTCs) is prognostic of poor outcome. Non-cancer cells in the tumor microenvironment (TME) play pivotal roles in breast cancer metastasis. We found a population of non-cancer, TME cells -- Cancer Associated Fibroblasts (CAFs) -- in circulation (cCAFs) of breast cancer patients. CAFs reside in the TME and critically contribute to breast cancer progression, stemness, immune suppression, drug resistance, and ultimately metastasis. Importantly, the presence of CAFs in the circulation, in clusters with CTCs, supports the notion that cancer cells take their “soil” with them to new non-breast sites, to both protect them while in circulation and help them establish metastases. A recent study demonstrated that FGF-2 secreted by CAFs activated PR in the luminal BC cells. Thus, we hypothesize that CAF cross-talk with luminal BC cells induces activation of PR and PR-driven stemness and tamoxifen resistance, and ultimately metastasis/recurrence. We further hypothesize that circulating cancer cells, or cancer stem cells, alone or in co-clusters with cCAFs, in patients with tamoxifen-resistant/recurrent disease will exhibit activated PR expression in them. Overarching Challenges: (1) To identify why some breast cancers become life-threatening metastases: Building on our novel observations (i.e., activated PR drives both stemness and tamoxifen-resistance of luminal BC cells, elevated cCAF and cCAF/CTC cluster counts associate with advanced/metastatic BC, and CAFs form coclusters preferentially with cancer stem cells [CSCs]), we think that there is a causal relationship between CAFs, activated PR, and stemness and tamoxifen resistance, and thus recurrent/metastatic luminal BC. (2) Revolutionize treatment regimens by replacing them with ones that are more effective and less toxic: Understanding the CAF/phospho-PR cross-talk will identify potential targets for inhibition of CAF-driven activation of PR such as the FGF2 axis, stemness, and tamoxifen resistance that then in combination with less toxic anti-progestins would have enhanced efficacy in the treatment of tamoxifen-resistant/recurrent luminal BC. Types of patients it will help and how it will help them: Luminal (ER+/PR+) breast cancer patients with tamoxifen-resistant/recurrent disease. Inhibition of PR and CAF factors that activate it would potentially block stemness and tamoxifen resistance/recurrence. Potential clinical applications, benefits, and risks: Understanding PR cross-talk with s
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910700
Entities
People
- Dorraya El-ashry
Organizations
- United States Army
- University of Minnesota