**6.3 Activation of ERα**

*Hormone Therapy and Replacement in Cancer and Aging-Related Diseases*

This also helps to avoid side effects related to estrogen deficiency [50].

androgen receptor ligand, 5α-dihydrotestosterone [51].

**6.2 Selective estrogen receptor modulators (SERMs)**

and/or corepressors to the receptor [52].

suppression of tumor cell proliferation [53].

Finasteride and dutasteride (5α-reductase enzyme inhibitors) are found to inhibit 5α-reductase-mediated conversion of testosterone to the high affinity

Estrogen is chemically related compounds derived from androgen precursors but contain a defining aromatic and hydroxyl group at the 17th position. Estrogens comprise the natural ligands for estrogen receptors (ERs), with 17β-estradiol being a potent agonist. 17β-estradiol has been reported to inhibit metastasis-associated lung adenocarcinoma transcript 1 (MALAT-1)-mediated osteosarcoma migration, invasion, metastasis, and induction of cell apoptosis, in an estrogen receptor α (ERα)-independent manner [15]. Earlier it was thought that binding of ER agonists induces a conformational change in the receptors, conferring the ability for coactivators to bind, whereas ER antagonists were thought to compete for binding [52]. But later studies with tamoxifen revealed that the same molecule can behave as an agonist (tamoxifen acts as an estrogen agonist in the uterus, promoting hypertrophy) as well as an antagonist (tamoxifen exhibited estrogenic activity in the bone, thus protecting against bone loss), depending on the tissue context. Recently it has been found that oxysterols such as 27-hydroxycholesterol (27 HC) also modulate the activity of estrogen receptors (ERs) and are therefore classified as endogenous SERMs. 27 HC is derived from cholesterol in the presence of enzyme CYP27A1 (cytochrome P450 enzyme). Breast cancer is the most common cancer in women, and its metastasis is majorly hormone (estrogen receptor) dependent. Some of the reports emphasize on the role of 27 HC in cancer progression and drug resistance, but several other reports also highlight its beneficial role in inhibiting proliferation and invasion of prostate cancer cells by blocking sterol-regulatory element-binding protein 2 (SREBP2). However, their different affinities for the different subtypes of ERs (α and β) and different relative expressions of these subtypes in tissues may explain some the of SERMs' pharmacology. Recent evidence also suggests that binding of the receptor even by structurally related compounds could result in unique conformational changes, thus allowing recruitment of distinct sets of co-activators

SERMs such as genistein, daidzein, and 4-hydroxytamoxifen have been reported

to downregulate the expression of epidermal growth factor (EGFR) in vitro in osteosarcoma cells in an ER-dependent manner. The reduction in EGFR expression resulted in upregulation of markers for osteoblast differentiation, thus resulting in

Isoflavones such as genistein and daidzein are abundantly found in soybeans and soy-based food products. Isoflavones, coumestans, and lignans belong to a

ADT is the mainstay of treatment for advanced prostate cancer, but eventual development of castration-resistant prostate cancer (CRPC) reduces the survival rates. One of the main reasons for development of CRPC is the sustained levels of androgen within the tumor due to suboptimal androgen suppression by primary ADT. Moreover, apart from the hormone-independent subsets, the other subsets of CRPC cells adapt themselves to the low testosterone environment induced by ADT and become hypersensitive to even lower concentrations of testosterone and other androgen precursors. Therefore, secondary hormone therapies are proving to be more efficient to achieve maximum suppression of testosterone. GTx-758 (3-fluoro-N-(4-fluorophenyl)-4-hydroxy-N-(4-hydroxyphenyl) benzamide) is an oral nonsteroidal selective estrogen receptor (ERα) agonist that lowers the free testosterone and PSA levels by increasing sex hormone-binding globulin (SHBG).

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Osteosarcoma is a malignant tumor in the bone that originates from osteoblasts or osteoblast precursors. The reports clarify that normal osteoblasts express ERα, whereas osteosarcomas do not (due to promoter DNA methylation). Thus a treatment strategy that involves induction of ERα expression in osteosarcoma cells in combination with estrogen administration would reduce proliferation of osteosarcoma and increase cell differentiation. In vitro treatment of osteosarcoma cells with decitabine (DAC, 5-Aza-2′-deoxycytidine) has been found to induce the expression of ERα but reduce the expression of metastasis-associated markers such as vimentin, slug, zeb1, and MMP9, with simultaneous decrease in stem cell markers such as *SOX2*, *OCT4*, and *NANOG*. Subsequent treatment with 17β-estradiol synergized with DAC in reducing cell proliferation and inducing differentiation markers such as alkaline phosphatase, osterix, and bone sialoproteins [21].

### **6.4 Estrogen inhibitors**

The bone is the frequent site for metastasis of breast cancer. Estrogen plays a critical role in development and progression of breast cancer by interacting with ERα and ERβ. In postmenopausal women, estrogens (estrone and estradiol) are synthesized from androgens (androstenedione and testosterone) at extragonadal sites, including the breast. Thus the third generation of therapy involves inhibition of these aromatase enzymes, catalyzing the conversion of androgens to estrogens [56]. The aromatase inhibitors fall into two categories: steroidal and nonsteroidal. Letrozole and anastrozole are the third-generation nonsteroidal aromatase inhibitors that block the extragonadal conversion of androgens to estrogens and give rise to an estrogen-depleted environment [51, 56, 57]. This lowers the estrogen in breast tissues and reduces their metastasis to the bone [56]. But in patients with hormone receptor-positive breast cancer, both the disease and its therapeutic treatment with antiestrogenic agents negatively impact the bone and result in decrease in bone mineral density. Therefore anti-hormonal therapy is considered only in cases where cancer cells express the ERα [58]. However, unlike nonsteroidal aromatase inhibitors, a steroidal aromatase inhibitor, e.g., exemestane (probably due to its steroid structure), has been reported to exert beneficial effects on the bone through its primary metabolite 17-hydroexemestane [51, 57].

Fulvestrant, an alkylosulfonian derivative of estradiol, is another category of estrogen inhibitors (estrogen receptor antagonist), which competitively binds to ER with high affinity and downregulates expression of ERβ by functional blockade [59, 60]. Fulvestrant has been reported to induce mitochondrial depolarization at high concentrations that results in release of apoptogenic factors, loss of oxidative phosphorylation, and eventually cell death due to apoptosis [60].

2-Methoxyestradiol (2-ME) belongs to another class of anticancer drugs, which act via induction of neuronal nitric oxide synthase and generation of nitric oxide

in the nuclei of cancer cells. However, recently 2-ME has been found to activate epigenetically silenced ERβ, resulting in apoptosis of malignant cancer cells [60].

Furthermore, some of the recent reports emphasize the role of mutant ERα gene (*ESR1*) in cancer progression and drug resistance. These mutations have been observed to get accumulated in circulating DNA of bone metastasis patients [32].

#### **6.5 Estrogen replacement**

Zoledronic acid is a known anti-resorptive agent and exhibits antitumor effects in ER-ve breast cancers. Some of the recent studies emphasize that it's the menopausal status (and not the hormone receptor status) that determines its anticancer efficiency [61]. This differential effect of zoledronic acid in pre- and postmenopausal bone metastasis patients has been suggested to be regulated by bone turnover effect of estrogen. Estrogen inhibits osteoclastogenesis via its direct effect on osteoclast and their precursors. Similarly, zoledronic acid also exhibits pro-apoptotic effects on osteoclasts by inhibiting mevalonate pathway and thus prevents release of growth factors that stimulate tumor growth. But in contrast to estrogen, zoledronic acid also reduces the number and activity of osteoblasts. Therefore, replacement of estrogen with zoledronic acid could be a more effective antitumor therapy in a low-estrogen bone microenvironment. Though administration of zoledronic acid does not alter growth of ER+ve cells at the primary site of tumor, it hampers their dissemination in the bone. As the cells evade the bone microenvironment, zoledronic acid-mediated bone turnover inhibits their proliferation and prevents overt metastases. Thus zoledronic acid could inhibit bone metastases of both ER-ve and ER+ve breast cancer cells [61].

One of the study reports dealing with in vitro microarray data analysis revealed that glucocorticoid was more efficient in controlling osteosarcoma cell growth than 17β estradiol. Glucocorticoid upregulated the expression of tumor suppressor genes resulting in apoptosis and downregulated the oncogenes associated with cell cycle and mitosis, whereas estradiol had an opposite action [62].

## **7. Conclusion**

Primary bone tumors are a rare occurrence, and most of the bone tumors arise due to metastases of breast, prostate, or lung cancers. The bone is the preferred site for metastases because of its highly vascular nature and extensive molecular signaling. A large number of bone tumor cases have been observed in an adolescent population experiencing a growth spurt and hormonal changes. Therefore, the treatment methodologies for bone tumors rarely involve the use of hormones as drugs but rather deal with hormone deprivation or inhibition. Though therapeutic approaches involving deprivation or replacement of hormones negatively affect bone health, the hormonal therapy alone or in combination with chemotherapeutic drugs offers a promising strategy for inhibition of bone tumors and improving the survival rates.

## **Acknowledgements**

This article reflects collective intellectual wisdom of the authors. We thank Savitribai Phule Pune University, Pune, India, for providing the necessary infrastructure during the compilation of this chapter. We also thank our colleagues, whose work has been cited in this article, for their inspiration.

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**Author details**

provided the original work is properly cited.

Pune, India

Geetanjali B. Tomar\*, Jay R. Dave, Sayali S. Chandekar and Suhas T. Mhaske Institute of Bioinformatics and Biotechnology, Savitribai Phule Pune University,

\*Address all correspondence to: geetanjalitomar13@gmail.com; joshigeet@gmail.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

*Bone Tumors: Types and Treatments*

**Conflict of interest**

*DOI: http://dx.doi.org/10.5772/intechopen.86550*

The authors declare no conflict of interest with relation to this study.
