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RANK is a poor prognosis marker and a therapeutic target in ER-negative postmenopausal breast cancer.

ABSTRACT: Despite strong preclinical data, the therapeutic benefit of the RANKL inhibitor, denosumab, in breast cancer patients, beyond the bone, is unclear. Aiming to select patients who may benefit from denosumab, we hereby analyzed RANK and RANKL protein expression in more than 2,000 breast tumors (777 estrogen receptor-negative, ER^- ) from four independent cohorts. RANK protein expression was more frequent in ER^- tumors, where it associated with poor outcome and poor response to chemotherapy. In ER^- breast cancer patient-derived orthoxenografts (PDXs), RANKL inhibition reduced tumor cell proliferation and stemness, regulated tumor immunity and metabolism, and improved response to chemotherapy. Intriguingly, tumor RANK protein expression associated with poor prognosis in postmenopausal breast cancer patients, activation of NFKB signaling, and modulation of immune and metabolic pathways, suggesting that RANK signaling increases after menopause. Our results demonstrate that RANK protein expression is an independent biomarker of poor prognosis in postmenopausal and ER^- breast cancer patients and support the therapeutic benefit of RANK pathway inhibitors, such as denosumab, in breast cancer patients with RANK⁺ ER^- tumors after menopause.

SUBMITTER: Ciscar M

PROVIDER: S-EPMC10086586 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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RANK is a poor prognosis marker and a therapeutic target in ER-negative postmenopausal breast cancer.

Ciscar Marina M Trinidad Eva M EM Perez-Chacon Gema G Alsaleem Mansour M Jimenez Maria M Jimenez-Santos Maria J MJ Perez-Montoyo Hector H Sanz-Moreno Adrian A Vethencourt Andrea A Toss Michael M Petit Anna A Soler-Monso Maria T MT Lopez Victor V Gomez-Miragaya Jorge J Gomez-Aleza Clara C Dobrolecki Lacey E LE Lewis Michael T MT Bruna Alejandra A Mouron Silvana S Quintela-Fandino Miguel M Al-Shahrour Fatima F Martinez-Aranda Antonio A Sierra Angels A Green Andrew R AR Rakha Emad E Gonzalez-Suarez Eva E

EMBO molecular medicine 20230307 4

Despite strong preclinical data, the therapeutic benefit of the RANKL inhibitor, denosumab, in breast cancer patients, beyond the bone, is unclear. Aiming to select patients who may benefit from denosumab, we hereby analyzed RANK and RANKL protein expression in more than 2,000 breast tumors (777 estrogen receptor-negative, ER<sup>-</sup> ) from four independent cohorts. RANK protein expression was more frequent in ER<sup>-</sup> tumors, where it associated with poor outcome and poor response to ...[more]

PMID: 36880458

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Project description:BACKGROUND:In breast cancer, activation of bone morphogenetic protein (BMP) signaling and elevated levels of BMP-antagonists have been linked to tumor progression and metastasis. However, the simultaneous upregulation of BMPs and their antagonist, and the fact that both promote tumor aggressiveness seems contradictory and is not fully understood. METHODS:We analyzed the transcriptomes of the metastatic 66cl4 and the non-metastatic 67NR cell lines of the 4T1 mouse mammary tumor model to search for factors that promote metastasis. CRISPR/Cas9 gene editing was used for mechanistic studies in the same cell lines. Furthermore, we analyzed gene expression patterns in human breast cancer biopsies obtained from public datasets to evaluate co-expression and possible relations to clinical outcome. RESULTS:We found that mRNA levels of the BMP-antagonist Grem1, encoding gremlin1, and the ligand Bmp4 were both significantly upregulated in cells and primary tumors of 66cl4 compared to 67NR. Depletion of gremlin1 in 66cl4 could impair metastasis to the lungs in this model. Furthermore, we found that expression of Grem1 correlated with upregulation of several stem cell markers in 66cl4 cells compared to 67NR cells. Both in the mouse model and in patients, expression of GREM1 associated with extracellular matrix organization, and formation, biosynthesis and modification of collagen. Importantly, high expression of GREM1 predicted poor prognosis in estrogen receptor negative breast cancer patients. Analyses of large patient cohorts revealed that amplification of genes encoding BMP-antagonists and elevation of the corresponding transcripts is evident in biopsies from more than half of the patients and much more frequent for the secreted BMP-antagonists than the intracellular inhibitors of SMAD signaling. CONCLUSION:In conclusion, our results show that GREM1 is associated with metastasis and predicts poor prognosis in ER-negative breast cancer patients. Gremlin1 could represent a novel target for therapy.

Dataset Information

RANK is a poor prognosis marker and a therapeutic target in ER-negative postmenopausal breast cancer.

Publications

RANK is a poor prognosis marker and a therapeutic target in ER-negative postmenopausal breast cancer.

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