FOXM1 is a transcriptional target of ERα and has a critical role in breast cancer endocrine sensitivity and resistance

Abstract

not available at time of publication. Abstract not available at time of publication. Retrospective studies on male breast cancer (MBC) have suff ered from small numbers of cases available from any one centre; thus a signifi cant problem in eff ectively studying this disease is accruing suffi ciently large numbers to allow comparative analysis of biomarkers associated with response. Using a coordinated multicentre approach, we present the fi rst large-scale study to address the relevance of the expression of hormone receptors in MBC and female breast cancer (FBC) using immunohistochemistry combined with a novel bioinformatics approach. Following ethical approval, 523 archival blocks (260 MBCs and 263 matched FBCs) were obtained retrospectively. Tissue microarrays were constructed and sections stained for ERα, ERβ1, ERβ2, ERβ5, total PR, PRA, PRB and AR and typed using CK5/6, CK14, CK18 and CK19 by immunohistochemistry. Following scoring, a range of ordination techniques were conducted on the datasets including hierarchical clustering and principal component analysis (PCA) + ) were infrequent in both. Hierarchical clustering revealed common clusters between MBC and FBC including total PR-PRA-PRB and ERβ1/2 clusters. ERα occurred on distinct clusters between males and females. AR, ERβ1, ERβ2 and ERβ5 all existed on the same cluster but with a diff erent substructure, particularly around the positioning of AR. ERα associated with this cluster in the male but not the female group. PCA confi rmed that in both groups strong infl uences came from PR-PRA-PRB. In MBC strong infl uences additionally came from AR and ERβ1, ERβ2 and ERβ5, whereas in FBC strong infl uences came from ERα alone. Our data support the hypothesis that breast cancer is biologically diff erent in male and females, which could have implications for therapy. Introduction The response rarely sustains long among the responders for Herceptin (trastuzumab) monotherapy treatment. It is still poorly understood how Herceptin exerts its mechanism of action and how the acquired resistance to this drug occurs. Materials and methods We used a multidisciplinary approach including fl uorescence resonance energy transfer and biochemical methods to assess the eff ects of Herceptin on various signalling pathways and to determine the acquired resistance mechanisms of Herceptin in various HER2-positive breast cell lines and a BT474 xenograft model. Results We have shown that Herceptin does not decrease HER2 phosphorylation despite the eff ect on HER2 receptor downregulation. HER2 phosphorylation is maintained by the activation of EGFR, HER3 and HER4 via their dimerisation with HER2 in breast cancer cells. The activation of EGFR, HER3 and HER4 is induced by HER ligand release, including heregulin and betacellulin. The release of HER ligands is mediated by ADAM proteases including ADAM17/TACE. Furthermore, we demonstrated that the feedback loop involving HER ligands and ADAM proteases is activated due to a decrease in PKB phosphorylation induced by Herceptin t...

FOXM1 targets XIAP and Survivin to modulate breast cancer survival and chemoresistance

“…FOXM1 emerges as a potent oncogenic transcription factor closely involved in resistance to agents used in chemotherapeutic protocols in breast cancer (Carr et al, 2010;Kwok et al, 2010;Millour et al, 2010;Park et al, 2012;Khongkow et al, 2014). Although FOXM1 activates genes crucial for metastasis, angiogenesis, invasion and DNA repair , its role in the regulation of genes involved in survival and inhibition of apoptosis has not been explored.…”

“…FOXM1 overexpression is a common feature of most tumours , and often correlates with drug resistance (Carr et al, 2010;Kwok et al, 2010;Millour et al, 2010;Park et al, 2012;Khongkow et al, 2014) and poor outcome in breast cancer patients' samples (Martin et al, 2008;Yau et al, 2011). Apart from cell cycle genes, FOXM1 can transcriptionally activate genes involved in many other processes like angiogenesis (Ahmad et al, 2010;Karadedou et al, 2012), invasion (Ahmad et al, 2010), metastasis (Raychaudhuri and Park, 2011) and DNA damage repair Zona et al, 2014).…”

FoxM1 expression is significantly associated with cisplatin-based chemotherapy resistance and poor prognosis in advanced non-small cell lung cancer patients

“…It was first identified as a proliferation-specific transcription factor, which is expressed in various tumor cell lines and embryonic tissues [41,42]. Previous work has linked FoxM1 upregulation to a variety of cancers, including cancers of the liver, gastric, prostate, brain, breast, lung, esophagus, colon, pancreas and nervous system, marking it as a proto-oncogene [13,[18][19][20][21][22][23][24][25][26][27]43]. Genome-wide gene expression profiling of cancers has independently and consistently identified FoxM1 as one of the most commonly upregulated genes in human solid tumor [44][45][46].…”

“…It has been shown to play important roles in regulating the expression of genes involved in cell proliferation, differentiation, and transformation [17]. Increased expression of FoxM1 has been found in several human tumors suggesting a role in human carcinogenesis [13,[18][19][20][21][22][23][24][25][26][27]. Moreover, it has been shown that higher expression of FoxM1 was associated with poor prognosis of cancer patients and could serve as an independent predictor of poor survival in cancer [28][29][30][31][32][33][34].…”

Upregulated FoxM1 expression induced by hepatitis B virus X protein promotes tumor metastasis and indicates poor prognosis in hepatitis B virus-related hepatocellular carcinoma

“…FoxM1 levels were dramatically decreased in adult tissues, but FoxM1 expression was reactivated by oncogenic signaling pathways and reactive oxygen species, resulting in the malignant progression of numerous cancers [10,11]. We had previously reported that hypoxia induced FoxM1 expression and FoxM1 overexpression accelerated the growth and survival of cancer cells under hypoxic stress [12].…”