Endocrine-Related Cancer

Current adjuvant treatments for operable breast cancer include chemotherapy, endocrine therapy in hormone receptor-positive tumors, and trastuzumab for HER2-positive tumors. Metanalyses of randomized trials show that in patients with hormone receptor-positive breast cancer, the effects of endocrine therapy and chemotherapy on survival are non-mutually exclusive. Most of these patients are therefore considered candidates to combined treatment. Recently, however, the endocrine responsiveness of tumors has been redefined on clinical, histopathological, and molecular bases. An emerging concept is that as endocrine responsiveness increases, chemoresponsiveness decreases. In the adjuvant setting, therapeutic choices are often based on small projected improvements in clinical outcomes. As a consequence, the role of chemotherapy and traditional management algorithms in patients with hormone receptor positive is being challenged. This review will address the current controversy regarding the role of adjuvant chemotherapy, including the newer anthracycline and taxane-based programs, in these patients.

The gastroprokinetic agent metoclopramide is known to stimulate catecholamine secretion from pheochromocytomas. The aim of the study was to investigate the mechanism of action of metoclopramide and expression of serotonin type 4 (5-HT₄) receptors in pheochromocytoma tissues. Tissue explants, obtained from 18 pheochromocytomas including the tumor removed from a 46-year-old female patient who experienced life-threatening hypertension crisis after metoclopramide administration and 17 additional pheochromocytomas (9 benign and 8 malignant) were studied. Cultured pheochromocytoma cells derived from the patient who previously received metoclopramide were incubated with metoclopramide and various 5-HT₄ receptor ligands. In addition, total mRNAs were extracted from all the 18 tumors. Catecholamine- and granin-derived peptide concentrations were measured in pheochromocytoma cell incubation medium by HPLC and radioimmunological assays. In addition, expression of 5-HT₄ receptor mRNAs in the 18 pheochromocytomas was investigated by the use of reverse transcriptase-PCR. Results: Metoclopramide and the 5-HT₄ receptor agonist cisapride were found to activate catecholamine- and granin-derived peptide secretions by cultured tumor cells. Metoclopramide- and cisapride-evoked catecholamine- and granin-derived peptide productions were inhibited by the 5-HT₄ receptor antagonist GR 113808. 5-HT₄ receptor mRNAs were detected in the patient's tumor and the series of 17 additional pheochromocytomas. This study shows that pheochromocytomas express functional 5-HT₄ receptors that are responsible for the stimulatory action of metoclopramide on catecholamine- and granin-derived peptide secretion. All 5-HT₄ receptor agonists must therefore be contraindicated in patients with proven or suspected pheochromocytoma.

The function of estrogen receptor beta (ER-β) in mammary tissue is not completely understood. While early observations were often conflicting, more recent data suggest an important role as a tumor-suppressor gene. A decrease of ER-β expression has been observed in ductal carcinoma in situ and invasive carcinoma as compared with benign mammary epithelial cells. The loss of ER-β resulted in abnormal growth of mammary epithelial cells. We have previously shown that the mRNA expression of the ER-β gene is almost totally suppressed in breast carcinomas from patients with a poor prognosis. Here we analyzed whether methylation changes in the different promoters of ER-β are responsible for the loss of expression of the gene. A methylation assay with high specificity and sensitivity was developed, and a panel of breast tissue samples (n = 175) was characterized for methylation status. In contrast to benign breast, more than two-thirds of invasive breast cancers showed a high degree of methylation. Importantly, increased methylation was also detectable in numerous premalignant lesions. By analysis of breast tumors, previously characterized by gene-expression profiling, methylation was predominantly detected in a subgroup of patients with an unfavorable prognosis, suggesting a possible prognostic value of the ER-β methylation status. We also investigated the structural characteristics of the two ER-β promoters, which were both found to be closely associated with a second, downstream, localized and opposite-oriented promoter. However, we could not detect endogenous antisense RNA transcribed from these promoters, which may be involved in epigenetic gene silencing. We also failed to induce ER-β promoter methylation by expressing siRNAs in cell lines. Interestingly, by comparing the promoter sequences of ER-β with other genes known to be epigenetically inactivated in breast cancers, we identified a sequence motif possibly involved in promoter methylation.

The tumor microenvironment is best characterized as a fluctuation of hypoxia and nutrient deprivation, which leads to epigenetic and genetic adaptation of clones and increased invasiveness and metastasis. In turn, these hypoxic adaptations make the tumors more difficult to treat and confer increased resistance to current therapies. Part of this adaptation is the regulation of gene products in response to hypoxia. Many of these hypoxia-regulated genes are mediated by the hypoxia-inducible factor 1 (HIF-1) complex, which is composed of a heterodimer pair of HIF-1α and HIF-1β. This heterodimer binds to the promoter of hypoxia-responsive genes, while interacting with other transcription factors, such as p300, signal and transducer of transcription 3, and Redox effector factor 1/apurinic/apyrimidinic endonuclease. HIF-1α levels itself can be regulated by hypoxia transcriptionally and post-translationally through ubiquitination; but the magnitude of the response is modulated by several other pathways, including free radicals that affect crosstalk with HIF-1α/HIF-1β transcriptional activities. HIF-1α has emerged as an important transcription factor in breast cancer and prostate cancer biology, and is expressed in the early stages of mammary and prostate carcinogenesis. Its expression is correlated with diagnostic and prognostic indicators for early relapse and metastatic disease, thus making HIF-1α a potential prognostic biomarker in proteomic assessments of breast and prostate cancers. The importance of HIF-1α in tumor progression makes it a logical target for chemoprevention strategies in patients at higher genetic risk of breast and prostate cancer with Cox 2 inhibitors or 2-methoxyestradiol, as well as a target for new approaches to inhibiting angiogenesis. The crosstalk between estrogen signaling pathways and HIF-1α is still not fully defined in breast cancer, but downstream estrogen receptor signaling may be a candidate for estrogen modulation of HIF-1α levels. In prostate cancer, androgens upregulate HIF-1α through androgen-regulated autocrine receptor tyrosine kinase receptor signaling. This review will put into perspective the role of HIF-1α in endocrine oncology and present new data on HIF-1α signaling and the potential for targeted therapies, including combinatory hormonal therapies.

Endocrine organs are metastatic targets for several primary cancers, either through direct extension from nearby tumour cells or dissemination via the venous, arterial and lymphatic routes. Although any endocrine tissue can be affected, most clinically relevant metastases involve the pituitary and adrenal glands with the commonest manifestations being diabetes insipidus and adrenal insufficiency respectively. The most common primary tumours metastasing to the adrenals include melanomas, breast and lung carcinomas, which may lead to adrenal insufficiency in the presence of bilateral adrenal involvement. Breast and lung cancers are the most common primaries metastasing to the pituitary, leading to pituitary dysfunction in approximately 30% of cases. The thyroid gland can be affected by renal, colorectal, lung and breast carcinomas, and melanomas, but has rarely been associated with thyroid dysfunction. Pancreatic metastasis can lead to exo-/endocrine insufficiency with renal carcinoma being the most common primary. Most parathyroid metastases originate from breast and lung carcinomas and melanoma. Breast and colorectal cancers are the most frequent ovarian metastases; prostate cancer commonly affects the testes. In the presence of endocrine deficiencies, glucocorticoid replacement for adrenal and pituitary involvement can be life saving. As most metastases to endocrine organs develop in the context of disseminated disease, surgical resection or other local therapies should only be considered to ameliorate symptoms and reduce tumour volume. Although few consensus statements can be made regarding the management of metastases to endocrine tissues because of the heterogeneity of the variable therapies, it is important that clinicians are aware of their presence in diagnosis.

Inhibin and activin are members of the transforming growth factor beta (TGFbeta) family of cytokines produced by the gonads, with a recognised role in regulating pituitary FSH secretion. Inhibin consists of two homologous subunits, alpha and either betaA or betaB (inhibin A and B). Activins are hetero- or homodimers of the beta-subunits. Inhibin and free alpha subunit are known products of two ovarian tumours (granulosa cell tumours and mucinous carcinomas). This observation has provided the basis for the development of a serum diagnostic test to monitor the occurrence and treatment of these cancers. Transgenic mice with an inhibin alpha subunit gene deletion develop stromal/granulosa cell tumours suggesting that the alpha subunit is a tumour suppressor gene. The role of inhibin and activin is reviewed in ovarian cancer both as a measure of proven clinical utility in diagnosis and management and also as a factor in the pathogenesis of these tumours. In order to place these findings into perspective the biology of inhibin/activin and of other members of the TGFbeta superfamily is also discussed.

Estrogens and insulin-like growth factors (IGFs) act as mitogens promoting cell proliferation in normal breast tissue as well as in breast carcinomas. Both hormones have been shown to play a role in the development of breast cancer and were found to activate multiple signaling pathways leading to proliferation of human breast cancer cell lines in vitro. Originally, it was considered that these agents manifest their mitogenic actions through separate pathways, but a growing body of evidence suggests that the IGF- and estrogen-mediated signaling pathways are intertwined. 17beta-Estradiol (E2) has been shown to enhance IGF signaling at multiple levels. E2 treatment of breast cancer cells alters expression of nearly all of the IGF family members including IGF-I, IGF-II, IGF-binding proteins, IGF type I receptor (IGF-RI), and insulin receptor substrate 1. The ligand-bound estrogen receptor has been reported to bind to and to activate the IGF-RI directly. Vice versa, IGF signaling has been reported to enhance estrogen receptor activation in human breast cancer cells by inducing phosphorylation of the estrogen receptor. Finally, several groups have described synergistic effects of the combination of E2 and IGF-I on S phase entry in breast tumor cell lines. Here, we review recent, often contradictory, reports describing the effects of E2 and IGFs on the proliferation of breast tumor cells, with special emphasis on the synergistic effects of the two hormones.

Androgen receptor splice variants are alternatively spliced variants of androgen receptor, which are C-terminally truncated and lack the canonical ligand-binding domain. Accumulating evidence has indicated a significant role of androgen receptor splice variants in mediating resistance of castration-resistant prostate cancer to current therapies and in predicting therapeutic responses. As such, there is an urgent need to target androgen receptor splicing variants for more effective treatment of castration-resistant prostate cancer. Identification of precise and critical targeting points to deactivate androgen receptor splicing variants relies on a deep understanding of how they are generated and the mechanisms of their action. In this review, we will focus on the emerging data on their generation, clinical significance and mechanisms of action as well as the therapeutic influence of these findings.