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Giorgio Secreto, Alessandro Girombelli, and Vittorio Krogh

The aim of this review is to highlight the pivotal role of androgen excess in the development of breast cancer. Available evidence suggests that testosterone controls breast epithelial growth through a balanced interaction between its two active metabolites: cell proliferation is promoted by estradiol while it is inhibited by dihydrotestosterone. A chronic overproduction of testosterone (e.g. ovarian stromal hyperplasia) results in an increased estrogen production and cell proliferation that are no longer counterbalanced by dihydrotestosterone. This shift in the androgen/estrogen balance partakes in the genesis of ER-positive tumors. The mammary gland is a modified apocrine gland, a fact rarely considered in breast carcinogenesis. When stimulated by androgens, apocrine cells synthesize epidermal growth factor (EGF) that triggers the ErbB family receptors. These include the EGF receptor and the human epithelial growth factor 2, both well known for stimulating cellular proliferation. As a result, an excessive production of androgens is capable of directly stimulating growth in apocrine and apocrine-like tumors, a subset of ER-negative/AR-positive tumors. The key role of androgen excess in the genesis of different subtypes of breast cancer has significant clinical implications for both treatment and prevention. Our belief stems from a thorough analysis of the literature, where an abundance of evidence is present to justify a clinical trial that would investigate the effectiveness of treating the underlying excessive androgen production.

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Daniel Medina

The ovarian hormones, estrogen and progesterone, play a pivotal role in normal and neoplastic development of the mammary gland. These hormones have a paradoxical role as long duration of estrogen and progesterone are associated with increased breast cancer risk, while short duration of pregnancy level doses are associated with a reduced breast cancer risk. The protective effects of estrogen and progesterone, as well as pregnancy, have been extensively studied in animal models. Recent studies have demonstrated that these hormones induce alterations in gene expression in the mammary epithelial cells which persist for a long time after the hormones are withdrawn from the host. It is postulated that hormones induce a switch in mammary developmental fate which decreases the risk of breast cancer over the lifetime of the host. Some of the possible cellular pathways persistently altered by short term hormone exposure are a decrease in growth factors and an increase in apoptosis. The expression of these genes, in turn, may be affected by alterations in genes regulating chromatin remodeling. The relative contributions of host-mediated factors and mammary cell intrinsic factors remain to be determined. The current studies have moved this research area from the biological to the molecular realm and offer the potential for directing prevention efforts at specific molecular targets.

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F Labrie

Breast cancer is the most frequently diagnosed and the second cause of cancer death in women, thus making breast cancer a most feared disease. Since breast cancer metastasizes early and it is unlikely that improvements in the treatment of metastatic disease could permit a cure in most cases in the foreseeable future, it is clear that prevention is essential in order practically to eliminate deaths from breast cancer. Tamoxifen is the only selective estrogen receptor modulator (SERM) currently registered for use in breast cancer prevention; the tamoxifen versus raloxifene study should indicate the efficacy of this compound compared with raloxifene. The recent benefits of aromatase inhibitors over tamoxifen indicate the advantages of a blockade of estrogens more complete than the one achieved with tamoxifen, a SERM having some estrogenic activity in the mammary gland and an even higher estrogenic action in the uterus. However, it is unlikely that the general estrogen ablation achieved with aromatase inhibitors will be acceptable for the long-term use required for prevention. It is thus important to develop SERMs with highly potent and pure antagonistic activity in the mammary gland and uterus while possessing estrogen-like activity in tissues of particular importance for women’s health, namely the bones and the cardiovascular system. However, it is expected that a SERM alone will not meet all the requirements of women’s health at the postmenopause when ovarian estrogen secretion has ceased and peripheral formation of androgens and estrogens from DHEA by intracrine mechanisms is decreased by 60% or more. One possibility is to combine a SERM with DHEA, a precursor of sex steroids that permits, somewhat like SERMs, tissue-specific formation of androgens and/or estrogens according to the level of expression of the steroidogenic and steroid-inactivating enzymes. DHEA could thus compensate for the important loss of androgens that accompanies aging and could also permit sex steroid formation and action in the brain while breast cancer prevention would be achieved by the SERM.

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Kellie L Jones and Aman U Buzdar

Breast cancer is the most common carcinoma diagnosed in women today excluding non-melanoma skin cancers. It has been well documented that estrogen plays a critical role in its development and is a major target for treatment. For many years, tamoxifen has been the gold standard for adjuvant hormonal therapy in breast cancer patients. With newer products targeting different mechanisms to suppress estrogen production, patients now have many decisions regarding their care. Agents such as luteinizing hormone releasing hormone (LHRH) agonists can suppress ovarian function in premenopausal patients and have been shown to be as effective and even better than chemotherapy (CMF — cyclophosphamide, methotrexate, fluorouracil-containing regimens) in certain patient populations. Tamoxifen continues to be an option as well as toremifene, a similar selective estrogen receptor modulator. With the advent of newer third generation aromatase inhibitors (anastrozole, letrozole and exemestane) toxicities have been documented to be less and in some cases they are more efficacious than the standard, tamoxifen. This article reviews the current data regarding ovarian suppression, ovarian suppression plus tamoxifen, tamoxifen, toremifene, anastrozole, letrozole, and exemestane in the treatment of adjuvant hormonal-sensitive breast cancer.

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A Brodie, Q Lu, Y Liu, and B Long

The potential of aromatase (estrogen synthetase) within the breast to provide a significant source of estrogen mediating tumor proliferation is suggested by studies reporting 4- to 6-fold higher estrogen levels in tumors than in plasma of postmenopausal patients with breast cancer. Recent studies in our laboratory have identified aromatase and its mRNA in tumor epithelial cells using immunocytochemistry and in situ hybridization. In addition, significant aromatase activity, which was stimulated 7-fold by dexamethasone, was measured in metastatic cells isolated from a breast cancer patient. Increase in proliferation, as measured by proliferating cell nuclear antigen immunostaining in tumor sections and by thymidine incorporation into DNA in response to testosterone, was observed in histocultures of breast cancer samples. This latter effect could be inhibited by 4-hydroxyandrostenedione. These results imply that intratumoral aromatase has functional significance and may be an important target for successful inhibitor treatment of breast cancer patients. To investigate treatment strategies with aromatase inhibitors and antiestrogens, we developed an intratumoral aromatase model to simulate the hormone responsive postmenopausal breast cancer patient. Tumors of estrogen receptor positive human breast carcinoma cells (MCF-7) transfected with the human aromatase gene are grown in ovariectomized nude mice. These cells synthesize sufficient estrogen to stimulate tumor formation. We have utilized this model to investigate the effects on tumor growth of the antiestrogens, tamoxifen and ICI 182780, and the aromatase inhibitors, letrozole and anastrozole (arimidex), alone and in combination. Both the aromatase inhibitors and the antiestrogens were effective in suppressing tumor growth. However, letrozole was significantly more effective than the antiestrogens. When the aromatase inhibitors were combined with the antiestrogen, tamoxifen, tumor growth was suppressed to about the same extent as with the aromatase inhibitors alone. Furthermore, the results do not suggest any benefit from combining tamoxifen with the pure antiestrogen, ICI 182780. Thus sequential use of these agents is likely to be more advantageous to the patient in terms of longer duration of effective treatment.

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Shelby M King, Tyvette S Hilliard, Lucia Y Wu, Randal C Jaffe, Asgerally T Fazleabas, and Joanna E Burdette

Ovarian cancer is the most lethal gynecological malignancy affecting American women. Current hypotheses concerning the etiology of ovarian cancer propose that a reduction in the lifetime number of ovulations decreases ovarian cancer risk. Advanced serous carcinoma shares several biomarkers with fallopian tube epithelial cells, suggesting that some forms of ovarian carcinoma may originate in the fallopian tube. Currently, the impact of ovulation on the tubal epithelium is unknown. In CD1 mice, ovulation did not increase tubal epithelial cell (TEC) proliferation as measured by bromodeoxyuridine incorporation and proliferating cell nuclear antigen staining as compared to unstimulated animals. In superovulated mice, an increase in the number of pro-inflammatory macrophages was detected in the oviduct. Ovulation also increased levels of phospho-γH2A.X in TEC, indicating that these cells were susceptible to double-strand DNA breakage following ovulation. To determine which components of ovulation contributed to DNA damage in the fallopian tube, an immortalized baboon TEC cell line and a three-dimensional organ culture system for mouse oviduct and baboon fallopian tubes were developed. TEC did not proliferate or display increased DNA damage in response to the gonadotropins or estradiol alone in vitro. Oxidative stress generated by treatment with hydrogen peroxide or macrophage-conditioned medium increased DNA damage in TEC in culture. Ovulation may impact the fallopian tube epithelium by generating DNA damage and stimulating macrophage infiltration but does not increase proliferation through gonadotropin signaling.

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R R Tekmal, N Kirma, K Gill, and K Fowler

To test directly the role of breast-tissue estrogen in initiation of breast cancer, we have developed the aromatase-transgenic mouse model and demonstrated for the first time that increased mammary estrogens resulting from the overexpression of aromatase in mammary glands lead to the induction of various preneoplastic and neoplastic changes that are similar to early breast cancer. Continued overexpression of aromatase that leads to increased breast-tissue estrogen contributes to a number of epigenetic changes in mammary tissue such as alteration in the regulation of genes involved in apoptosis, activation of genes involved in cell cycle and cell proliferation, and activation of a number of growth factors. Our current studies show aromatase overexpression is sufficient to induce and maintain early preneoplastic and neoplastic changes in female mice without circulating ovarian estrogen. Preneoplastic and neoplastic changes induced in mammary glands as a result of aromatase overexpression can be completely abrogated with the administration of the aromatase inhibitor, letrozole. Consistent with complete reduction in hyperplasia, we have also seen downregulation of estrogen receptor and a decrease in cell proliferation markers, suggesting aromatase-induced hyperplasia can be treated with aromatase inhibitors. Our studies demonstrate that aromatase overexpression alone, without circulating estrogen, is responsible for the induction of breast hyperplasia and these changes can be abrogated using aromatase inhibitors.

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Zane Hammoud, Bailin Tan, Sunil Badve, and Robert M Bigsby

Numerous epidemiological observations point to sex differences in lung cancer etiology and progression. The present study was aimed at understanding the bases of these sex differences. To test the effect of estradiol on tumor progression, we used a mouse model based on conditional Kras expression and concurrent deletion of Tp53 following inhalation of an adenoviral vector expressing Cre recombinase (AdeCre). Ovariectomized females and males were treated with estradiol via a continuous-release capsule. Tumor multiplicity, tumor volume, and histological grade were determined at 10 weeks after AdeCre administration. Cell proliferation was monitored by Ki67 immunohistochemistry at 4 and 10 weeks after AdeCre administration. At 10 weeks, female mice had more than twice the number of tumors evident on the surface of the lungs than male mice; ovariectomy eliminated this sex difference. The estrogen treatment significantly increased tumor number and volume in ovariectomized females and in males. Histological character of the tumors ranged from adenoma to adenocarcinoma. Ovary-intact females exhibited higher grade tumors than ovariectomized females or males. Progression to higher histological grade was stimulated by estrogen in male mice but not in ovariectomized females. At 10 weeks after AdeCre administration, tumor cell Ki67-labeling varied widely, precluding assessment of an estrogen effect; however, at 4 weeks, Ki67 labeling of lung parenchymal cells was increased 3.5-fold by estrogen. In conclusion, estrogen acts as a promoter for lung adenocarcinoma in a genetically defined lung cancer model; estrogen-induced cell proliferation in the oncogene-initiated cells is likely to play a role in this tumor promoter activity.

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Sisi He, Liqian Ma, Amy E Baek, Anna Vardanyan, Varsha Vembar, Joy J Chen, Adam T Nelson, Joanna E Burdette, and Erik R Nelson

There is an urgent need for more effective strategies to treat ovarian cancer. Elevated cholesterol levels are associated with a decreased progression-free survival time (PFS) while statins are protective. 27-Hydroxycholesterol (27HC), a primary metabolite of cholesterol, has been shown to modulate the activities of the estrogen receptors (ERs) and liver x receptors (LXRs) providing a potential mechanistic link between cholesterol and ovarian cancer progression. We found that high expression of CYP27A1, the enzyme responsible for the synthesis of 27HC, was associated with decreased PFS, while high expression of CYP7B1, responsible for 27HC catabolism, was associated with increased PFS. However, 27HC decreased the cellular proliferation of various ovarian cancer cell lines in an LXR-dependent manner. Intriguingly, ID8 grafts were unable to effectively establish in CYP27A1−/− mice, indicating involvement of the host environment. Tumors from mice treated with 27HC had altered myeloid cell composition, and cells from the marrow stem cell lineage were found to be responsible for the effects in CYP27A1−/− mice. While inhibition of CYP27A1 or immune checkpoint did not significantly alter tumor size, their combination did, thereby highlighting this axis as a therapeutic target.

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R A Stein and D P McDonnell

The orphan receptor estrogen-related receptor α (ERRα) is a member of the nuclear receptor superfamily of ligand-regulated transcription factors. This protein is structurally most related to the canonical estrogen receptor and has been shown to modulate estrogen signaling in some contexts. These observations have heightened interest in ERRα as a therapeutic target in both breast and ovarian cancer and in other estrogenopathies. This review details our present understanding of ERRα action with a view to highlight specific aspects of its signal-transduction pathway in breast cancer that may be amenable to pharmaceutical manipulation.