Proto-oncogene PIM-1 is a novel estrogen receptor target associating with high grade breast tumors

• Published in: Molecular and cellular endocrinology 2013-01, Vol.365 (2), p.270-276
• Main Authors: Malinen, Marjo, Jääskeläinen, Tiina, Pelkonen, Mikko, Heikkinen, Sami, Väisänen, Sami, Kosma, Veli-Matti, Nieminen, Kaisa, Mannermaa, Arto, Palvimo, Jorma J.
• Format: Article
• Language: English
• Subjects: 17β-estradiol; Breast cancer; breast neoplasms; Breast Neoplasms - metabolism; Breast Neoplasms - mortality; Breast Neoplasms - pathology; carcinogenesis; Carcinoma, Ductal, Breast - metabolism; Carcinoma, Ductal, Breast - mortality; Carcinoma, Ductal, Breast - pathology; Carcinoma, Lobular - metabolism; Carcinoma, Lobular - mortality; Carcinoma, Lobular - pathology; Case-Control Studies; Cell growth; cell proliferation; Cyclin-Dependent Kinases - genetics; Cyclin-Dependent Kinases - metabolism; estradiol; Estradiol - physiology; Estrogen receptor (ER) α; Estrogen Receptor alpha - physiology; estrogen receptors; Female; Gene Expression; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; MCF-7 Cells; neoplasm cells; Neoplasm Grading; PIM-1; protein kinases; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Proto-Oncogene Proteins c-pim-1 - genetics; Proto-Oncogene Proteins c-pim-1 - metabolism; proto-oncogenes; RNA, Small Interfering - genetics
• ISSN: 0303-7207; 1872-8057
• DOI: 10.1016/j.mce.2012.10.028

► Proto-oncogene PIM-1 is regulated by estrogen in MCF-7 breast cancer cells. ► The expression level of PIM-1 contributes to the growth of MCF-7 cells. ► Elevated PIM-1 expression is associated with a higher breast cancer grade. We searched ERα cistromes of MCF-7 breast cancer cells for previously unrecognized ERα targets and identified proto-oncogene PIM-1 as a novel potential target gene. We show that the expression of PIM-1 is induced in response to estradiol in MCF-7 cells and that the induction is mediated by ERα-regulated enhancers located distally upstream from the gene. In keeping with the growth-promoting role of the PIM-1, depletion of the PIM-1 attenuated the proliferation of the MCF-7 cells, which was paralleled with up-regulation of cyclin-dependent protein kinase inhibitor CDKN1A and CDKN2B expression. Analysis of PIM-1 expression between invasive breast tumors and benign breast tissue samples showed that elevated PIM-1 expression is associated with malignancy and a higher tumor grade. In sum, identification of PIM-1 as an ERα target gene adds a novel potential mechanism by which estrogens can contribute to breast cancer cell proliferation and carcinogenesis.