Steroid hormone mimics: molecular mechanisms of cell growth and apoptosis in normal and malignant mammary epithelial cells

doi:10.1016/S0960-0760(01)00186-8

The Journal of Steroid Biochemistry and Molecular Biology

Volume 80, Issue 2, February 2002, Pages 191-201

https://doi.org/10.1016/S0960-0760(01)00186-8 Get rights and content

Abstract

Anti-estrogen (anti-E2) therapy with E2 receptor antagonists has a significant benefit in women with breast cancer, but it may also increase the risk for developing hormone-independent breast cancer for which there is no therapy similar to that used in hormone-dependent breast cancer. Therefore, there is a significant interest in the development of compounds that may provide therapeutic benefit for hormone-independent breast cancer without untoward risks and adverse effects. The estrogen receptor (ER) modulators with both agonistic as well as antagonistic properties may, thus, be exploited for the development of the next generation of compounds for the prevention and/or treatment of breast cancer. In this article, we have discussed the clinical indications, risks, benefits and mechanisms of action of ER modulators and related compounds, particularly indole-3-carbinol (I3C), which may open new avenues for the prevention and/or treatment of breast cancer.

Introduction

Breast cancer is the most frequently diagnosed cancer among women in the western world, with approximately 180,000 new cases identified annually in USA alone. It is currently the second leading cause of cancer related mortality in women in USA. The ultimate goal for studying breast cancer biology is to make an impact in the reduction in mortality by identifying those women who are either at high risk for the development of the disease or by predicting the prognosis of patients who are treated for breast cancer with multi-modality therapy.

Cancer may be considered a disorder of cell proliferation and differentiation. Approximately 25% of new cancers arise in tissues whose development and function is strongly dependent on steroid hormones (breast, endometrium and prostate). Epidemiological evidence also strongly implicates a number of hormones in the development of several types of human tumors. The interaction of hormone and growth factors with cancer cells demonstrates that some malignant cells may respond partially to physiological control mechanisms, however, others may not, suggesting the heterogeneous complexity of this disease. The treatment of breast cancer cells with anti-hormone therapy is one of the effective options among many treatment modalities, however, significant interactions between hormone and growth factors may be an important determinant for breast cancer therapy, especially in patients with hormone-independent disease.

Given this perspective, we intend to provide some evidence in this article regarding the complex interactions between growth factors/growth factors receptors, steroid hormone/steroid hormone receptors and steroid hormone mimics in the regulation of cell growth and apoptosis in normal and malignant breast epithelial cells and their implications.

Section snippets

Steroid hormone and its receptors

Only specialized cells in the adrenal gland, ovary or testis are a major source for the synthesis of steroid hormones. In addition, breast tissue composed of different cell types also contributes to the local production of steroid hormones, particularly estrogen (E2), during normal development of the organ as well as during breast carcinogenesis. The majority of breast cancers in post-menopausal women are initially hormone-dependent, however, a significant proportion of pre-menopausal breast

Interaction of hormone and growth factors

E2 and progesterone are closely associated with breast epithelial proliferation, tumorigenesis and malignant progression in vivo. Studies in vivo and in vitro suggest that steroid and polypeptide hormone may act through mechanisms that involve the production and release of growth factors. The growth factors may self-stimulate the growth of breast cancer cells directly via autocrine, paracrine, juxtracrine or intracrine pathways regulated by complex interactions of epithelial cells with stromal

Tamoxifen for prevention of breast cancer

Although there are several biological sub-classifications of invasive breast cancer, breast cancer is primarily classified into the following two categories: ER/PR positive or ER/PR negative tumors. E2 plays an important role and may be initially driving the tumor growth in an ER-dependent manner. During the invasive growth of the tumor, however, a certain percentage of these tumors becomes ER negative and thus, grow in an E2-independent manner. In addition, tumor cells with the expression of

Molecular signaling pathway and E2

E2 plays a significant and critical role in a variety of biological processes and is believed to be responsible for controlling the growth and survival of most breast cancer cells. Under in vivo selection during the development of invasive breast cancer, an E2-dependent breast cancer may become E2-independent [14]. The molecular mechanism(s) for this progression to E2 independence is not completely understood. There are several molecular signaling pathways that are believed to be responsible

The role of E2 mimics

As indicated earlier, tamoxifen can reduce the recurrence of ER positive tumors by 69%, but made no difference in the recurrence of ER negative tumors [13]. It is clear that tamoxifen can be used successfully to prevent E2-dependent growth of breast cancer [12], [13], but there are no alternative therapeutic strategies for the reduction in the recurrence of E2-independent growth of breast cancer. However, there are several known naturally occurring biological compounds, which may be potentially

The relevance and the role of I3C in breast cancer

Our previously published results, along with our current ongoing investigations, which applied state-of-the-art molecular techniques, are aimed at examining the tumor-suppressive effects and mechanism(s) of action of diet derived agents on breast cancer cells [63], [79]. Because the mechanism(s) underlying the origin and the evolution of breast cancer are poorly understood, it is generally accepted that during the initial stages of tumor development, E2 play at least a permissive role and for

Perspective

In this perspective, we have tried to summarize the current literature and present our understanding of E2/ER signaling, role and mechanisms of anti-E2 in breast cancer therapy as well as interactions between steroid hormone signaling and growth factor signaling. During the complex interactions of hormones and growth factors with cancer, malignant cells may respond physiologically to the control mechanisms triggered by the natural/synthetic chemopreventive systems. A deeper insight into these

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These compounds are known to modulate multiple signaling pathways leading to their observed biological effects. A plethora of information is available in literature documenting the effects of indole compounds, I3C, and DIM on several distinct signaling pathways.8,14–25 Modulation of NF-κB pathway is considered central to the anticancer activity of indole compounds15,26,27 because inhibition of NF-κB signaling pathway not only plays an important role in effective induction of apoptosis by these compounds but also leads to sensitization of aggressive cancer cells to conventional chemotherapeutics.
Indole compounds, obtained from cruciferous vegetables, are known to possess potent anticancer properties. Studies with indole-3-carbinol (I3C) and its dimeric product, 3,3’ diindolylmethane (DIM), have indicated the efficacy of these compounds against a number of human cancers, which is related to their ability to interfere with and modulate multiple cellular signaling pathways. The nuclear factor-kappa B (NF-κB) pathway plays an important role in the control of cell proliferation, metastasis, angiogenesis, and drug resistance. Emerging evidence points to an effective inhibition of NF-κB signaling by I3C and DIM. This seems to be central to most of the observed anticancer properties of these compounds. Here, we summarize our current understanding of regulation of NF-κB signaling by I3C and DIM and the resulting biological effects. Breast, prostate, and pancreatic cancers are relatively better characterized in terms of modulation of NF-κB signaling by indoles, and it is our intent that this review incites similar studies in other human cancer models as well.
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The effects of progesterone (P), testosterone (T), chlormadinone acetate (CMA), medroxyprogesterone acetate (MPA), norethisterone (NET), levonorgestrel (LNG), dienogest (DNG), gestodene (GSD) and 3-ketodesogestrel (KDG) were investigated in normal human breast epithelial MCF10A cells. In addition, the effects of these steroids were tested in estrogen and progesterone receptor positive HCC1500 human primary breast cancer cells.
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Steroid hormone mimics: molecular mechanisms of cell growth and apoptosis in normal and malignant mammary epithelial cells

Abstract

Introduction

Section snippets

Steroid hormone and its receptors

Interaction of hormone and growth factors

Tamoxifen for prevention of breast cancer

Molecular signaling pathway and E2

The role of E2 mimics

The relevance and the role of I3C in breast cancer

Perspective

J. Biol. Chem.

Pathol. Res. Pract.

J. Biol. Chem.

Exp. Cell Res.

J. Steroid Biochem. Mol. Biol.

Obstet. Gynecol.

Lancet

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

FEBS Lett.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Otolaryngol. Head Neck Surg.

Chem. Biol. Interact.

Chem. Biol. Interact.

J. Biol. Chem.

Hormone-dependent interaction between the amino- and carboxyl-terminal domains of progesterone receptor in vitro and in vivo

Mol. Endocrinol.

Novel mechanisms of progesterone antagonists and progesterone receptor

J. Soc. Gynecol. Invest.

The opposing transcription activities of the two isoforms of the human progesterone receptor are due to differential cofactor binding

Mol. Cell. Biol.

High-mobility group chromatin proteins 1 and 2 functionally interact with steroid hormone receptors to enhance their DNA binding in vitro and transcriptional activity in mammalian cells

Mol. Cell. Biol.

Interaction of oestrogen receptor with the regulatory sub-unit of phosphatidylinositol-3-OH kinase

Nature

Oestrogen receptor-α variant mRNA expression in primary human breast tumours and matched lymph node metastasis

Br. J. Cancer

Steroid hormones in endometrial and breast cancer: review

Eur. J. Gynaecol. Oncol.

c-erbB2 mRNA expression in human breast tumours: comparison with c-erbB2 DNA amplification and correlation with prognosis

Br. J. Cancer

Basic science of HER-2/ν: a review

Semin. Oncol.

HER-2 expression and response to tamoxifen in estrogen receptor positive breast cancer: a Southwest Oncology Group study

Clin. Cancer Res.

Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 study

J. Natl. Cancer Inst.

Activation of the unliganded estrogen receptor by EGF involves the MAP kinase pathway and direct phosphorylation

EMBO J.

Inhibition of HER2/ν (erbB-2) and mitogen-activated protein kinases enhances tamoxifen action against HER2-overexpressing, tamoxifen-resistant breast cancer cells

Cancer Res.

Estrogen-induced mitogenesis of MCF7 cells does not require the induction of mitogen-activated protein kinase activity

J. Steroid Biochem. Mol. Biol.

Elevated mitogen-activated protein kinase activity in estrogen non-responsive human breast cancer cells

Cancer Res.

Transforming growth factor-β in breast cancer: a working hypothesis

Breast Cancer Res. Treat.

Augmentation of the response of normal mammary epithelial cells to estradiol by mammary stroma

Cancer Res.

Inhibition of mitogen-activated protein kinase and phosphatidylinositol 3-kinase activity in MCF7 cells prevents estrogen-induced mitogenesis

Cell Growth Differ.

Molecular mechanism of a cross-talk between oestrogen and growth factor signaling pathways

Genes Cells

Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase

Science

From HER2/ν signal cascade to androgen receptor and its co-activators: a novel pathway by induction of androgen target genes through MAP kinase in prostate cancer cells

Proc. Natl. Acad. Sci. U.S.A.

A mechanism for hormone-independent prostate cancer through modulation of androgen receptor signaling by the HER-2/ν tyrosine kinase

Nat. Med.

Human breast cancer: correlation of relapse and survival with amplification of the HER-2/ν oncogene

Science

Interaction of phosphatidylinositol 3-kinase-associated p85 with epidermal growth factor and platelet-derived growth factor receptors

Mol. Cell. Biol.