BreastDefend enhances effect of tamoxifen in estrogen receptor-positive human breast cancer in vitro and in vivo

Shujie Cheng,Daniel Sliva,Mark Alvarado,Isaac Eliaz,Victor Castillo,George E Sandusky,Matt Welty,Constance J Temm

doi:10.1186/s12906-017-1621-7

Abstract

BackgroundTamoxifen (TAM) has been widely used for the treatment of estrogen receptor (ER)-positive breast cancer and its combination with other therapies is being actively investigated as a way to increase efficacy and decrease side effects. Here, we evaluate the therapeutic potential of co-treatment with TAM and BreastDefend (BD), a dietary supplement formula, in ER-positive human breast cancer.MethodsCell proliferation and apoptosis were determined in ER-positive human breast cancer cells MCF-7 by MTT assay, quantitation of cytoplasmic histone-associated DNA fragments and expression of cleaved PARP, respectively. The molecular mechanism was identified using RNA microarray analysis and western blotting. Tumor tissues from xenograft mouse model were analyzed by immunohistochemistry.ResultsOur data clearly demonstrate that a combination of 4-hydroxytamoxifen (4-OHT) with BD lead to profound inhibition of cell proliferation and induction of apoptosis in MCF-7 cells. This effect is consistent with the regulation of apoptotic and TAM resistant genes at the transcription and translation levels. Importantly, TAM and BD co-treatment significantly enhanced apoptosis, suppressed tumor growth and reduced tumor weight in a xenograft model of human ER-positive breast cancer.ConclusionBD sensitized ER-positive human breast cancer cells to 4-OHT/TAM treatment in vitro and in vivo. BreastDefend can be used in an adjuvant therapy to increase the therapeutic effect of tamoxifen in patients with ER-positive breast cancer.

Highlights

Tamoxifen (TAM) has been widely used for the treatment of estrogen receptor (ER)-positive breast cancer and its combination with other therapies is being actively investigated as a way to increase efficacy and decrease side effects
For in vitro cell culture assays assessing the effect of BD on the ER activity, MCF-7 cells were stripped of steroids for 3 days before seeding by culturing in steroid-free medium (SFM): phenol red-free DMEM, supplemented with 10% newborn calf serum (NCS), penicillin (50 U ml−1), streptomycin (50 U ml−1) and 4 mM L-Glutamine
We show that the low concentration of BD only slightly decreased proliferation of normal breast cells MCF-10A, whereas BD strongly suppressed growth of breast cancer cells MCF-7 and MDA-231 (Fig. 1a)

Summary

Introduction

Tamoxifen (TAM) has been widely used for the treatment of estrogen receptor (ER)-positive breast cancer and its combination with other therapies is being actively investigated as a way to increase efficacy and decrease side effects. We evaluate the therapeutic potential of co-treatment with TAM and BreastDefend (BD), a dietary supplement formula, in ER-positive human breast cancer. As the leading cause of cancer death in females, breast cancer is a heterogeneous disease that can be divided into three major subtypes: hormone (estrogen/progesterone) receptor-positive, HER2-positive, and triple-negative (estrogen, progesterone receptor and HER2-negative) [1, 2]. Estrogen receptor (ER)-positive breast tumors comprise approximately 75%, depending on estrogen signaling for growth and survival [3, 4]. In order to improve efficacy of the treatment and

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