The forkhead transcription factor FOXM1 promotes endocrine resistance and invasiveness in estrogen receptor-positive breast cancer by expansion of stem-like cancer cells

Abstract

IntroductionThe forkhead transcription factor FOXM1 coordinates expression of cell cycle-related genes and plays a pivotal role in tumorigenesis and cancer progression. We previously showed that FOXM1 acts downstream of 14-3-3ζ signaling, the elevation of which correlates with a more aggressive tumor phenotype. However, the role that FOXM1 might play in engendering resistance to endocrine treatments in estrogen receptor-positive (ER+) patients when tumor FOXM1 is high has not been clearly defined yet.MethodsWe analyzed FOXM1 protein expression by immunohistochemistry in 501 ER-positive breast cancers. We also mapped genome-wide FOXM1, extracellular signal-regulated kinase 2 and ERα binding events by chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) in hormone-sensitive and resistant breast cancer cells after tamoxifen treatment. These binding profiles were integrated with gene expression data derived from cells before and after FOXM1 knockdown to highlight specific FOXM1 transcriptional networks. We also modulated the levels of FOXM1 and newly discovered FOXM1-regulated genes and examined their impact on the cancer stem-like cell population and on cell invasiveness and resistance to endocrine treatments.ResultsFOXM1 protein expression was high in 20% of the tumors, which correlated with significantly reduced survival in these patients (P = 0.003 by logrank Mantel-Cox test). ChIP-seq analyses revealed that FOXM1 binding sites were enriched at the transcription start site of genes involved in cell-cycle progression, maintenance of stem cell properties, and invasion and metastasis, all of which are associated with a poor prognosis in ERα-positive patients treated with tamoxifen. Integration of binding profiles with gene expression highlighted FOXM1 transcriptional networks controlling cell proliferation, stem cell properties, invasion and metastasis. Increased expression of FOXM1 was associated with an expansion of the cancer stem-like cell population and with increased cell invasiveness and resistance to endocrine treatments. Use of a selective FOXM1 inhibitor proved very effective in restoring endocrine therapy sensitivity and decreasing breast cancer aggressiveness.ConclusionsCollectively, our findings uncover novel roles for FOXM1 and FOXM1-regulated genes in promoting cancer stem-like cell properties and therapy resistance. They highlight the relevance of FOXM1 as a therapeutic target to be considered for reducing invasiveness and enhancing breast cancer response to endocrine treatments.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-014-0436-4) contains supplementary material, which is available to authorized users.

Overexpression of FOXM1 Is a Potential Prognostic Marker in Male Breast Cancer

“…We found FOXM1 to be expressed in 94% of the tumors and highly expressed in 37% of cases. Interestingly, these results show that FOXM1 is more expressed in male than in female breast cancer, since previous studies demonstrated that 87% of female breast tumors express FOXM1 and 20% of these were classified as high-expression [26,27]. This confirms the aggressive phenotype of male breast cancer.…”

“…Furthermore, many studies demonstrated that FOXM1 contributes to all hallmarks of cancer [19,20], which explains the numerous emerging studies indicating FOXM1 as an important target for cancer therapy in the near future that offers exciting prospects [21][22][23][24]. Overexpression of FOXM1 has been reported in a large variety of human cancers including female breast cancer [25][26][27], and it correlated with tumor progression and poor prognosis [28]. However, the prognostic value of FOXM1 overexpression in male breast cancer remains unknown.…”

Association between FOXM1 and hedgehog signaling pathway in human cervical carcinoma by tissue microarray analysis

“…FOXM1 is a dynamic cancer-associated biomarker involved in the regulation of various biological processes, including cell cycle progression, differentiation, metastasis, invasion and angiogenesis (14)(15)(16)(17)(18). In a previous study, the present authors demonstrated that FOXM1 was overexpressed in cervical cancer tissues, and its nuclear expression was observed to be correlated with the pathological grade of the tumor (19).…”

Inhibitory effects of forkhead box L1 gene on osteosarcoma growth through the induction of cell cycle arrest and apoptosis

“…The role of FOX proteins in various types of cancer has been comprehensively investigated considering that these proteins have vital functions on biological processes. Certain Fox members including FOXP1, FOXM1, FOXR1 and FOXA1, show a diversity of activities on tumorigenesis and progression of cancer (4)(5)(6)(7)(8), while having dual roles in cancer biology. For instance, on the one hand, FOXP1 overexpression by chromosome translocations is associated with poor prognosis in lymphomas, suggesting it acts as an oncogene (4).…”