Targeting sex steroid biosynthesis for breast and prostate cancer therapy

Poutanen, Matti; Hagberg Thulin, Malin; Härkönen, Pirkko

doi:10.1038/s41568-023-00609-y

Cited by 8 publications

(1 citation statement)

References 337 publications

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“…Indeed, endocrine therapies have been widely attempted for breast and prostate cancer prevention, by inhibiting binding of sex steroids and their receptors to block downstream gene regulation and tumor cell growth. 367 Females with high-risk breast cancer are recommended to use selective estrogen receptor modulators, such as tamoxifen and raloxifene, or aromatase inhibitors, which inhibit aromatization of androgens and decrease the level of estrogens, but specific adverse events need considerations, including fracture, thrombosis, endometrial cancer, and cataract. 368 , 369 In placebo-controlled randomized trials, tamoxifen can reduce the incidence of breast cancer by 31%, while raloxifene, aromatase inhibitors, exemestane and anastrozole, reduce it by 56% and 55%, respectively.…”

Section: Cancer Risk Prediction and Intervention Strategiesmentioning

confidence: 99%

Tumor initiation and early tumorigenesis: molecular mechanisms and interventional targets

Zhang,

Xiao,

et al. 2024

Sig Transduct Target Ther

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Tumorigenesis is a multistep process, with oncogenic mutations in a normal cell conferring clonal advantage as the initial event. However, despite pervasive somatic mutations and clonal expansion in normal tissues, their transformation into cancer remains a rare event, indicating the presence of additional driver events for progression to an irreversible, highly heterogeneous, and invasive lesion. Recently, researchers are emphasizing the mechanisms of environmental tumor risk factors and epigenetic alterations that are profoundly influencing early clonal expansion and malignant evolution, independently of inducing mutations. Additionally, clonal evolution in tumorigenesis reflects a multifaceted interplay between cell-intrinsic identities and various cell-extrinsic factors that exert selective pressures to either restrain uncontrolled proliferation or allow specific clones to progress into tumors. However, the mechanisms by which driver events induce both intrinsic cellular competency and remodel environmental stress to facilitate malignant transformation are not fully understood. In this review, we summarize the genetic, epigenetic, and external driver events, and their effects on the co-evolution of the transformed cells and their ecosystem during tumor initiation and early malignant evolution. A deeper understanding of the earliest molecular events holds promise for translational applications, predicting individuals at high-risk of tumor and developing strategies to intercept malignant transformation.

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Section: Cancer Risk Prediction and Intervention Strategiesmentioning

confidence: 99%

Tumor initiation and early tumorigenesis: molecular mechanisms and interventional targets

Zhang,

Xiao,

et al. 2024

Sig Transduct Target Ther

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Enzalutamide Sensitizes Castration‐Resistant Prostate Cancer to Copper‐Mediated Cell Death

Gao,

Zhao,

Liu

et al. 2024

Advanced Science

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Despite the initial efficacy of enzalutamide in castration‐resistant prostate cancer (CRPC), inevitable resistance remains a significant challenge. Here, the synergistic induction of copper‐dependent cell death (cuproptosis) in CRPC cells is reported by enzalutamide and copper ionophores (elesclomol/disulfiram). Mechanistically, enzalutamide treatment increases mitochondrial dependence in CRPC cells, rendering them susceptible to cuproptosis, as evidenced by specific reversal with the copper chelator tetrathiomolybdate. This susceptibility is characterized by hallmarks of cuproptosis, including lipoylated protein aggregation and iron‐sulfur cluster protein instability. Interestingly, the mitochondrial matrix reductase, FDX1, specifically correlates with elesclomol sensitivity, suggesting a potential mechanistic divergence between the two copper ionophores. Notably, this synergistic effect extends beyond in vitro models, demonstrating efficacy in 22Rv1 xenografts, mouse Pten p53 knockout organoids. Importantly, enzalutamide significantly enhances copper ionophore‐mediated cytotoxicity in enzalutamide‐resistant cells. Collectively, these findings indicate that enzalutamide and copper ionophores synergistically induce cuproptosis, offering a promising therapeutic avenue for CRPC, potentially including enzalutamide‐resistant cases.

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Targeting the cancer cells and cancer‐associated fibroblasts with next‐generation FGFR inhibitors in prostate cancer co‐culture models

Afshan,

Kim,

Mattsson

et al. 2024

Cancer Medicine

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BackgroundInhibition of androgen receptor (AR) signaling is the main treatment strategy in advanced prostate cancer (PCa). A subset of castration resistant prostate cancer (CRPC) bypasses the AR blockade by increased fibroblast growth factor receptor (FGFR) signaling. The first‐ and second‐generation, non‐covalent FGFR inhibitors (FGFRis) have largely failed in the clinical trials against PCa. Purpose: In this study, we tested the drug sensitivity of LNCaP, VCaP, and CWR‐R1PCa cell lines to second‐generation, covalent FGFRis (FIIN1, FIIN2) and a novel FGFR downstream molecule inhibitor (FRS2αi).Methods2D and 3D mono‐ and co‐cultures of cancer cells, and cancer‐associated fibroblasts (CAFs) were used to mimic tumor‐stroma interactions in the extracellular matrix (ECM). The treatment responses of the FGFR signaling molecules, the viability and proliferation of cancer cells, and CAFs were determined through immunoblotting, migration assay, cell viability assay, and real‐time imaging. Immunofluorescent and confocal microscopy images of control and treated cultures of cancer cells and CAFs, and their morphometric data were deduced.ResultsThe FGFRis were more effective in mono‐cultures of the cancer cells compared with co‐cultures with CAFs. The FRS2αi was specifically effective in co‐cultures with CAFs but was not cytotoxic to CAF mono‐cultures as in the case of FIIN1 and FIIN2. At the molecular level, FRS2αi decreased p‐FRS2α, p‐ERK1/2, and activated apoptosis as monitored by cleaved caspase‐3 activity in a concentration‐dependent manner in the co‐cultures. We observed no synergistic drug efficacy in the combination treatment of the FGFRi with ARi, enzalutamide, and darolutamide. The FRS2αi treatment led to a decrease in proliferation of cancer cell clusters in co‐cultures as indicated by their reduced size and Ki67 expression.ConclusionsCAFs exert a protective effect on cancer cells and should be included in the in vitro models to make them physiologically more relevant in screening and testing of FGFRis. The FRS2αi was the most potent agent in reducing the viability and proliferation of the 3D organotypic co‐cultures, mainly by disrupting the contact between CAFs and cancer cell clusters. The next‐generation FGFRi, FRS2αi, may be a better alternative treatment option for overcoming ARi treatment resistance in advanced PCa.

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Targeting sex steroid biosynthesis for breast and prostate cancer therapy

Cited by 8 publications

References 337 publications

Tumor initiation and early tumorigenesis: molecular mechanisms and interventional targets

Tumor initiation and early tumorigenesis: molecular mechanisms and interventional targets

Enzalutamide Sensitizes Castration‐Resistant Prostate Cancer to Copper‐Mediated Cell Death

Targeting the cancer cells and cancer‐associated fibroblasts with next‐generation FGFR inhibitors in prostate cancer co‐culture models

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