Beta protein 1 homeoprotein induces cell growth and estrogen-independent tumorigenesis by binding to the estrogen receptor in breast cancer.

Sidney W Fu,Yan-Gao Man,Joseph J Pinzone,Samuel J Simmens,Sanket Awate,Christine Teal,Xiaohui Tan,Patricia E Berg,Barbara K Vonderhaar,Saurabh P Kirolikar,Arnold Schwartz,Erika Ginsburg

doi:10.18632/oncotarget.10633

Abstract

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.

Highlights

Beta Protein 1(BP1), an isoform of DLX4, belongs to the homeobox family of genes, master regulatory genes implicated in early development and cell differentiation that are frequently deregulated in cancer [1, 2]
By a number of different measures, MCF-7 cells overexpressing BP1 were more aggressive: they grew in the absence of serum, formed larger colonies in soft agar, were relatively more infiltrative in an invasion assay and could form tumors in mice without external estrogen supplementation
We demonstrated in our earlier study that overexpression of BP1 significantly enhanced cell proliferation and metastatic potential in estrogen receptor (ER)-negative Hs578T cells [15]

Summary

Introduction

Beta Protein 1(BP1), an isoform of DLX4, belongs to the homeobox family of genes, master regulatory genes implicated in early development and cell differentiation that are frequently deregulated in cancer [1, 2]. Repression of HOXA5 in breast cancer resulted in the loss of expression of the tumor suppressor p53 [4]. Constitutive expression of HOXA1 in MCF7 cells led to increased anchorage-independent growth and tumor formation in mice [5]. BP1 directly activates the anti-apoptotic gene BCL-2 and results in resistance to TNF-α. BP1 negatively regulates the expression of breast cancer anti-estrogen resistance 1 (BRCA1) through binding to its intron, suggesting that overexpression of BP1 might be a potential inhibitor of BRCA1. Targeting BP1 may provide a new avenue for breast cancer management [6]

Methods

Results

Conclusion