The potential role of mifepristone in breast cancer prevention: beyond medical abortion

Breast cancer is the leading cause of cancer-related deaths among women globally. Yet, current management strategies emphasise detection and treatment over primary prevention. For groups at high risk of breast cancer, such as carriers of BRCA1 or BRCA2 pathogenic variants, salpingo-oophorectomy and mastectomy are risk-reducing surgical options, but these approaches affect quality of life and evidence for a mortality benefit is sparse. Non-surgical treatments, such as selective oestrogen receptor modulators, have low efficacy against breast cancers with poor prognosis (eg, triple-negative cancers), and toxicity can often lead to poor adherence. Emerging evidence indicates that progesterone plays a part in breast carcinogenesis, particularly in carriers of BRCA1 pathogenic variants. Mifepristone, a selective progesterone receptor modulator, has shown potential to reduce breast epithelial proliferation. However, the association of this drug with medical abortion, besides long-standing availability and patent restrictions, has hindered its development for breast cancer prevention. Regulatory, political, and legal barriers, along with minimal pharmaceutical investment, have further restricted research. Collaborative efforts are needed to accelerate research on mifepristone as a non-surgical risk-reducing option. Overcoming current barriers is essential to expand prevention strategies, particularly for women at high risk of breast cancer worldwide

Confrontation of fibroblasts with cancer cells in vitro: Gene network analysis of transcriptome changes and differential capacity to inhibit tumor growth

Background: There is growing evidence that emerging malignancies in solid tissues might be kept under control by physical intercellular contacts with normal fibroblasts. Methods: Here we characterize transcriptional landscapes of fibroblasts that confronted cancer cells. We studied four pairs of in vitro and ex vivo fibroblast lines which, within each pair, differed in their capacity to inhibit cancer cells. The natural process was modeled in vitro by confronting the fibroblasts with PC-3 cancer cells. Fibroblast transcriptomes were recorded by Affymetrix microarrays and then investigated using network analysis. Results: The network enrichment analysis allowed us to separate confrontation- and inhibition-specific components of the fibroblast transcriptional response. Confrontation-specific differences were stronger and were characterized by changes in a number of pathways, including Rho, the YAP/TAZ cascade, NF-kB, and TGF-beta signaling, as well as the transcription factor RELA. Inhibition-specific differences were more subtle and characterized by involvement of Rho signaling at the pathway level and by potential individual regulators such as IL6, MAPK8, MAP2K4, PRKCA, JUN, STAT3, and STAT5A. Conclusions: We investigated the interaction between cancer cells and fibroblasts in order to shed light on the potential mechanisms and explain the differential inhibitory capacity of the latter, which enabled both a holistic view on the process and details at the gene/protein level. The combination of our methods pointed to proteins, such as members of the Rho pathway, pro-inflammatory signature and the YAP1/TAZ cascade, that warrant further investigation via tools of experimental perturbation. We also demonstrated functional congruence between the in vitro and ex vivo models. © 2015 Alexeyenko et al

Tumor microenvironment : the paradoxical action of fibroblasts [Elektronisk resurs]

The term tumor refers to an abnormal and pathological tissue characterized by a massive cell growth; it comprises various populations of transformed and malignant cells. These cells cross-communicate with each other and with different types of cells in the surrounding microenvironment. The nature of communication and interactions within the tumor microenvironment (TME) directs the fate of transformed cells via inducing pro- or antitumorigenic signals. Consequently, these cells will either succeed or fail to progress into a malignant growth phenotype. In the TME, fibroblasts are considered as one of the major cellular compartments and the primary source of non-cellular elements, including the extracellular matrix (ECM) and soluble factors. It has been shown that tumor cells can recruit fibroblasts to induce growth-stimulatory signals. On the other hand, normal fibroblasts may also act as tumor growth repressors. However, these actions have not been thoroughly addressed. The results of this thesis demonstrate the dual functionality of fibroblasts in the TME. First, we examined the phenomenon, whereby the normal fibroblasts inhibit tumor growth and development. We found that fibroblasts reduced tumor cell proliferation and motility through two sets of signals, the first set involved transmembrane proteins and the ECM. The second set was only effective after induction of the first signal, and included soluble factors secreted upon direct contact of the fibroblasts and tumor cells. Next, we uncovered the signaling pathways that were involved in the process of tumor growth inhibition and fibroblasts activation. We revealed a switch in fibroblasts from tumor suppressive cells to ones characterized by tumor stimulatory functions. Genetic ablation of the RhoA gene in fibroblasts significantly reduced tumor cell proliferation and motility in vitro, and induced tumor cell clustering in 3D-collagen matrix. Loosing of the suppressive function was accompanied by gaining a tumor inducing ability, since RhoA deficient fibroblasts enhanced tumor initiation and development by a small number of PC3 prostate cancer cells injected subcutaneously into immunodeficient mice. In addition, knocking out the RhoA gene altered the cytoskeletal organization and reduced αSMA expression in fibroblasts. These changes conferred the cells stiffer but less contractile compared to control cells. Furthermore, upon the crosstalk with tumor cells, the RhoA deficient fibroblasts overexpressed several pro-inflammatory genes encoding for IL6, IL8, CXCL1, CXCL5, and CCL5. Such a biochemical and mechanical shift in the fibroblasts reflected their protumorigenic phenotype. Using patient-derived cancer-associated fibroblasts (CAFs). We demonstrated that CAFs rescued tumor cells from apoptosis and could even enhance their growth under cis-platinum treatment. Beside the molecular mechanistic results, this thesis introduces a comprehensive quantitative live-cell imaging tool to investigate tumor cellfibroblast interactions dynamically, providing the opportunity to measure and observe cellular proliferation, motility, and phenotypic plasticity simultaneously. Taken together, the current thesis uncovers two opposite effects of fibroblasts on tumor growth. These results emphasize the demand for targeting both CAFs and tumor cells to treat and cure cancer patients and may open novel avenues for cancer prevention approaches

Transcriptomic profile of normal breast tissue post-mifepristone treatment: secondary outcomes of a randomized controlled trial

Abstract Progesterone receptor antagonism is gaining attention due to progesterone’s recognized role as a major mitogen in breast tissue. Limited but promising data suggest the potential efficacy of antiprogestins in breast cancer prevention. The present study presents secondary outcomes from a randomized controlled trial and examine changes in breast mRNA expression following mifepristone treatment in healthy women. We analyzed 32 paired breast biopsies from 16 healthy premenopausal women at baseline and after two months of mifepristone treatment. In total, twenty-seven differentially expressed genes were identified, with enriched biological functions related to extracellular matrix remodeling. Notably, the altered gene signature induced by mifepristone in vivo was rather similar to the in vitro signature. Furthermore, this expression gene signature was associated with breast carcinogenesis and significantly correlated with progesterone receptor expression status in breast cancer, as validated in The Cancer Genome Atlas dataset using the R2 platform. The present study is the first to explore the breast transcriptome following mifepristone treatment in healthy breast tissue in vivo , enhancing the understanding of progesterone receptor antagonism and its potential protective effect against breast cancer by investigating its action in healthy breast tissue

UV radiation promotes melanoma dissemination mediated by the sequential reaction axis of cathepsins-TGF-beta 1-FAP-alpha

Background: Ultraviolet radiation (UVR) is the major risk factor for development of malignant melanoma. Fibroblast activation protein (FAP)-alpha is a serine protease expressed on the surface of activated fibroblasts, promoting tumour invasion through extracellular matrix (ECM) degradation. The signalling mechanism behind the upregulation of FAP-alpha is not yet completely revealed. Methods: Expression of FAP-alpha was analysed after UVR exposure in in vitro co-culture systems, gene expression arrays and artificial skin constructs. Cell migration and invasion was studied in relation to cathepsin activity and secretion of transforming growth factor (TGF)-beta 1. Results: Fibroblast activation protein-a expression was induced by UVR in melanocytes of human skin. The FAP-alpha expression was regulated by UVR-induced release of TGF-beta 1 and cathepsin inhibitors prevented such secretion. In melanoma cell culture models and in a xenograft tumour model of zebrafish embryos, FAP-alpha mediated ECM degradation and facilitated tumour cell dissemination. Conclusions: Our results provide evidence for a sequential reaction axis from UVR via cathepsins, TGF-beta 1 and FAP-alpha expression, promoting cancer cell dissemination and melanoma metastatic spread.Funding Agencies|Swedish Research Council; Welander-Finsen Foundation; Ostgotaregionens Cancer Foundation; Swedish Cancer Society; County Council of Ostergotland; Olle Engkvist Foundation</p