Beta protein 1 homeoprotein induces cell growth and estrogen-independent tumorigenesis by binding to the estrogen receptor in breast cancer
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Sidney W. Fu1,*, Saurabh P. Kirolikar2,*, Erika Ginsburg3, Xiaohui Tan1, Arnold Schwartz4, Samuel J. Simmens5, Yan-Gao Man6, Joseph J. Pinzone7, Christine Teal8, Sanket Awate2, Barbara K. Vonderhaar3, Patricia E. Berg2
1Department of Medicine, Division of Genomic Medicine, George Washington University, Washington, DC 20037, USA
2Department of Biochemistry and Molecular Medicine, George Washington University, Washington, DC 20037, USA
3Mammary Biology and Tumorigenesis Laboratory, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
4Department of Pathology, George Washington University Medical Center, Washington, DC 20037, USA
5Department of Epidemiology and Biostatistics, School of Public Health and Health Services, George Washington University, Washington, DC 20037, USA
6Department of Gynecologic and Breast Pathology, Armed Forces Institute of Pathology, Washington, DC 20306, USA
7David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA
8Department of Surgery, George Washington University, Washington, DC 20037, USA
*These authors contributed equally to this work
Patricia E. Berg, email: firstname.lastname@example.org
Keywords: homeobox gene, BP1, estrogen receptor, tamoxifen resistance, tumorigenesis
Received: January 18, 2016 Accepted: July 06, 2016 Published: July 16, 2016
Expression of Beta Protein 1 (BP1), a homeotic transcription factor, increases during breast cancer progression and may be associated with tumor aggressiveness. In our present work, we investigate the influence of BP1 on breast tumor formation and size in vitro and in vivo. Cells overexpressing BP1 showed higher viability when grown in the absence of serum (p < 0.05), greater invasive potential (p < 0.05) and formed larger colonies (p < 0.004) compared with the controls. To determine the influence of BP1 overexpression on tumor characteristics, MCF-7 cells transfected with either empty vector (V1) or overexpressor plasmids (O2 and O4) were injected into the fat pads of athymic nude mice. Tumors grew larger in mice receiving O2 or O4 cells than in mice receiving V1 cells. Moreover, BP1 mRNA expression levels were positively correlated with tumor size in patients (p = 0.01). Interestingly, 20% of mice injected with O2 or O4 cells developed tumors in the absence of estrogen, while no mice receiving V1 cells developed tumors. Several mechanisms of estrogen independent tumor formation related to BP1 were established. These data are consistent with the fact that expression of breast cancer anti-estrogen resistance 1 (BCAR1) was increased in O2 compared to V1 cells (p < 0.01). Importantly, O2 cells exhibited increased proliferation when treated with tamoxifen, while V1 cells showed growth inhibition. Overall, BP1 overexpresssion in MCF-7 breast cancer cells leads to increased cell growth, estrogen-independent tumor formation, and increased proliferation. These findings suggest that BP1 may be an important biomarker and therapeutic target in ER positive breast cancer.
Sidney W. Fu
Saurabh P. Kirolikar
Samuel J. Simmens
Joseph J. Pinzone
Barbara K. Vonderhaar
Patricia E. Berg
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