Regulation of the FOXM1 transcription factor by the estrogen receptor alpha at the protein level, in breast cancer

Abstract

Breast cancer is the most frequent type of cancer of women in the western world. Antiestrogens, including Tamoxifen (OHT) and Faslodex (ICI), are widely used in the endocrine treatment of breast cancer. However, the majority of breast cancers are either resistant to endocrine therapy or eventually become unresponsive to antiestrogen therapy. Better understanding of the molecular mechanisms that govern tumour proliferation, is therefore needed to develop new therapies for the disease. The Forkhead family of transcription factors plays an important role in regulating cell proliferation, cell death and differentiation.The estrogen receptor (ER) a positive breast carcinoma cell line MCF-7 and the ERa negative line MDA-MB-231 was used to study the potential regulation of the Forkhead member FOXM1 by ER. It was indicated that estrogen and ER regulate the expression of FOXM1 at the protein level. Since Forkhead proteins play an important role in regulating cell proliferation, cell death and differentiation, this study helps to explain some of the functions of ER in tumourigenesis, and the way these Forkhead proteins could be crucial targets for therapeutic strategies and/or markers for diagnosis and prognosis.

Keywords: Breast cancer; ER; FOXM1; FOXO3a; Forkhead.

Figure 1. Molecular structure of ER homodimer bound on DNA via its DNA-binding domains

Figure 2. The PI3-K/PKB signalling pathway contributing in cell survival, growth and proliferation, cell differentiation and motility. Caspase-9, Forkhead transcription factors(FKHR), c-AMP responsive element binding protein(CREB), Nuclear factor kB(NFkB), Bad and Glycogen synthase kinase 3(GSK-3), are some of the dowstrean targets of the PI3-K signalling pathway that contribute to the various functions of the cascade

Figure 3. The FOXM1 transcription factor regulates transcription of cell-cycle genes essential for G1/S and G2/M progression, chromosomal segregation and cytokinesis

Figure 4. MCF-7 ER-positive breast cancer cells treated with E2 up tp 72 hours. FOXM1, FOXO3a, ERα, PLK1 and cyclin B1 protein levels were analysed by Western blotting

Figure 5. MCF-7 ER-positive breast cancer cells treated with ICI up to 48 hours. FOXM1, FOXO3a, ERα, PLK1 and cyclin B1 protein levels were analysed by Western blotting

Figure 6. MDA-MB-231 ER-negative breast cancer cells treated with ICI up tp 48 hours. FOXM1, FOXO3a, ERα, PLK1 and cyclin B1 protein levels were analysed by Western blotting