Hormone-dependent Breast Tumors Research Articles

Male Breast Cancer: Therapy-Induced Toxicities, Psychological Distress, and Individual Patient Goals during Oncological Inpatient Rehabilitation

Introduction: Male breast cancer (MBC) is a rare malignancy that accounts for less than 1% of all cancers in men and less than 1% of all breast cancers worldwide. Understandably, due to the low incidence of this rare cancer, there is a lack of prospective clinical data. The aim of this retrospective study was the analysis of therapy-induced toxicities as well as the assessment of psychological distress in the affected men during oncological inpatient rehabilitation. Methods: Fifty-one MBC patients were evaluated for the presence of treatment-induced side effects, toxicities, and psychological distress (using German version of the 11-stage NCCN distress thermometer; cut-off ≥5) during oncological indoor rehabilitation. The collected data were checked for correlation with sociodemographic and clinical factors (SPSS 22). Results: The mean age was 62.0 ± 10.6 years, in 96% a hormone-dependent breast tumor (ER+), and in over 75%, overweight or obesity (BMI >25/>30) was diagnosed. Most reported side effects included weakness/fatigue (74.5%), arthralgia after surgery/chemotherapy (43.1%), chemotherapy-induced polyneuropathy (36.3%), and/or lymphedema (13.7%). Psychological distress was detected in 24 cases (47.0%; ≥5), in 13 cases even with significantly high levels (25.5%; ≥7). There was no correlation between psychological distress and clinical factors such as age, performed treatment (e.g., chemotherapy), or therapy-induced side effects (e.g., lymphedema) in our small collective. Conclusions: Psychological distress and somatic side effects are common in MBC. These data demonstrate the importance of routine screening for psychological distress and the high need for psycho-oncological therapy (regardless of gender) in multimodal oncological rehabilitation.

Synthesis, antitumor activity and in silico analyses of amino acid derivatives of artepillin C, drupanin and baccharin from green propolis

Breast cancer has the highest incidence and mortality in females, while prostate cancer has the second-highest incidence in males. Studies have shown that compounds from Brazilian green propolis have antitumor activities and can selectively inhibit the AKR1C3 enzyme, overexpressed in hormone-dependent prostate and breast tumors. Thus, in an attempt to develop new cytotoxic inhibitors against these cancers, three prenylated compounds, artepillin C, drupanin and baccharin, were isolated from green propolis to synthesize new derivatives via coupling reactions with different amino acids. All obtained derivatives were submitted to antiproliferative assays against four cancer cells (MCF-7, MDA MB-231, PC-3, and DU145) and two normal cell lines (MCF-10A and PNT-2) to evaluate their cytotoxicity. In general, the best activity was observed for compound6e, derived from drupanin, which exhibited half-maximal inhibitory concentration (IC50) of 9.6 ± 3 μM and selectivity index (SI) of 5.5 against MCF-7 cells.In silicostudies demonstrated that these derivatives present coherent docking interactions and binding modes against AKR1C3, which might represent a possible mechanism of inhibition in MCF-7 cells.

Pseurotin A as a novel suppressor of hormone dependent breast cancer progression and recurrence by inhibiting PCSK9 secretion and interaction with LDL receptor

Hypercholesterolemia has been documented to drive hormone-dependent breast cancer (BC) progression and resistance to hormonal therapy. Proprotein convertase subtilisin/kexin type-9 (PCSK9) regulates cholesterol metabolism through binding to LDL receptor (LDLR) and targeting the receptor for lysosomal degradation. Inhibition of PCSK9 is an established strategy to treat hypercholesterolemia. Pseurotin A (PS) is a unique spiro-heterocyclic γ-lactam alkaloid isolated from the fungus Aspergillus fumigatus. Preliminary studies indicated that PS lowered PCSK9 secretion in cultured HepG2 hepatocellular carcinoma cells, with an IC50 value of 1.20 μM. Docking studies suggested the ability of PS to bind at the PCSK9 narrow interface pocket that accommodates LDLR. Surface plasmon resonance (SPR) showed PS ability to inhibit the PCSK9-LDLR interaction at a concentration range of 10−150 μM. PS showed in vitro dose-dependent reduction of PCSK9, along with increased LDLR levels in hormone-dependent BT-474 and T47D breast cancer (BC) cell lines. In vivo, daily oral 10 mg/kg PS suppressed the progression of the hormone-dependent BT-474 BC cells in orthotopic nude mouse xenograft model. Immunohistochemistry (IHC) investigation of BT-474 breast tumor tissue proved the PS ability to reduce PCSK9 expression. PS also effectively suppressed BT-474 BC cells locoregional recurrence after primary tumor surgical excision. Western blot analysis showed decreased PCSK9 expression in liver tissues of PS-treated mice compared to vehicle-treated control group. PS treatment significantly reduced PCSK9 expression and normalized LDLR levels in collected primary and recurrent breast tumors at the study end. PS-treated mice showed reduced plasma cholesterol and 17β-estradiol levels. Inhibition of tumor recurrence was associated with significant reductions in plasma level of the human BC recurrence marker CA 15−3 in treated mice at the study end. Histopathological examination of various PS-treated mice organs indicated lack of metastatic tumor cells and any pathological changes. The results of this study provide the first evidence for the suppression of the hormone-dependent breast tumor progression and recurrence by targeting the PCSK9-LDLR axis. PS is a novel first-in-class PCSK9-targeting lead appropriate for the use to control hormone-dependent BC progression and recurrence.

Significance of the pineal gland hormone melatonin in maintaining the health of women of reproductive age (a review)

Introduction. Maintaining women's reproductive health is an important task that requires safe approaches based on the pathogenesis. More and more studies address the role of the pineal gland (epiphysis) hormone melatonin (МТ) in the functioning of the reproductive system, as well as the impact of МТ deficiency on the women’s health.Aim: to analyze and summarize the available literature about the role of the pineal gland hormone МТ in the pathogenesis of gynecological diseases in women of reproductive age (infertility, endometriosis, polycystic ovary syndrome, premenstrual syndrome), and also about the impact of МТ deficiency on the health of women working night shifts.Materials and methods. The relevant publications were searched in domestic (eLibrary, CyberLeninka.ru) and international (Pubmed, Cochrane Library) databases; we looked up the materials published in the recent 7 years. In our search, we prioritized the free access to full text articles. The selection of sources was limited to the period from 2012 to 2019.Results. МТ is involved in the development of follicles by causing the oocytes maturation, promoting the development of embryos, inhibiting the synthesis of steroids in the ovaries and, therefore, reducing the level of steroids in the blood. MT delays ovarian aging through a variety of mechanisms, including the antioxidant action, the maintenance of the due length of the telomere, the upregulated expression of the aging-related SIRT genes, and also the regulation of the ribosome functioning. As MT protects germ cells from oxidative stress, it is essential for normal ovulation, fertilization and further development of the embryo; this hormone has an impact on the duration of the woman's fertility and the onset of menopause. MT has a potential therapeutic effect on endometriosis. The oncostatic role of MT in hormone-dependent breast tumors has been described. Disruption of normal MT production during night shifts is associated with the risk of developing breast cancer in shift workers. MT deficiency leads to circadian desynchronosis and may cause both somatic disorders (metabolic syndrome, obesity, oncopathology) and neuroendocrine dysregulation of the female reproductive system.Conclusion. The variety of physiological functions of the pineal gland hormone MT emphasizes the pathogenetic role of its deficiency in many gynecological and somatic diseases. Of particular relevance is the increased risk of cardiovascular disorders, the development of metabolic syndrome and breast cancer in women who work night shifts. Therefore, it is important both to maintain normal endogenous level of MT and also use its therapeutic potential to maintain the health of women of reproductive age.

Development of an estrogen-dependent breast cancer co-culture model as a tool for studying endocrine disruptors

We developed an innovative co-culture system composed of Hs578t human mammary stromal-like cells and T47D hormone-dependent breast epithelial tumor cells as a representative in vitro model of the human hormone-dependent mammary tumor microenvironment. Hs578t cells expressed aromatase (CYP19) mainly via the healthy stromal CYP19 promoter I.4, but also to a lesser extent via the breast cancer-relevant promoters PII, I.3 and I.7, and produced estrogens from androgen precursors. These estrogens stimulated T47D cell proliferation and estrogen receptor-dependent expression of trefoil factor-1 (TFF1), which is known to stimulate mammary tumor cell proliferation and migration. Hs578t cells can also undergo a “promoter-switch” where the normally silent CYP19 promoters PII, I.3 and I.7 become activated, which mimics the in vivo situation in human breast cancer patients. This positive feedback loop is the hallmark of the hormone-dependent breast tumor microenvironment. Using the co-culture model we designed, we evaluated the promoter-specific expression of CYP19, expression of estrogen-dependent gene TFF1, and determined the effects exhibited by basil and fennel seed essential oils on steroidogenesis in the tumor microenvironment.

Abstract 4810: Olive oil-derived (-)-oleocanthal for prevention of breast cancer recurrence

Abstract Despite progress in BC therapy and improved survival rates, several breast cancer (BC) patients have poor recurrence-free rates. More than three million BC survivors are currently at the risk of disease recurrence without feasible preventive options. Surgical excision of early-stage confined breast tumors commonly used to minimize subsequent metastasis. Neoadjuvant and adjuvant therapeutic agents usually cannot prevent BC recurrence. There is a dire need to discover novel recurrence and metastasis inhibitory entities because clinical trials on early-stage cancer patients survival and metastases/recurrence reduction endpoint is not financially feasible and need large patients number. Mediterranean populations have less colon and breast cancers incidence due to their dietary consumption of significant amounts of phenolics-rich extra-virgin olive oil (EVOO). (-)-Oleocanthal (OC) is the most bioactive EVOO phenolic with diverse activities and exceptional in vivo potency. Validated molecular targets of OC in BC include the inhibition of the activation of the RTKs c-Met and HER2 and modulation of estrogen receptors (ER). Met/HER2/ER amplification is implicated in activation of quiescent breast tumor cells, repopulation, subsequent recurrence and relapse. This study reports the potent ability of four-weeks oral 10 mg/kg OC treatments to inhibit more than 90% of local and regional triple negative and hormone-dependent breast tumors recurrence after the surgical excision of orthotopically xenografted primary breast tumors. Oral OC treatments also potently inhibited recurrence after surgical excision of breast tumors subjected to neoadjuvant therapies with either lapatinib (50 mg/kg, 5X/week, 4 weeks) or paclitaxel (4.5 mg/kg, ip, 3X/week for 6 weeks) in athymic orthotopic nude mice models. This was associated with significant reductions of p-c-Met and p-HER2 levels in treated animal tumors by Western blotting. OC-treated mice sera completely lacked the BC recurrence marker CA 15-3, unlike vehicle treated controls which showed significantly high CA 15-3 levels. OC treatment did not show any observable toxicity and did not affect animals body weight over the experiment course. OC is a novel breast cancer recurrence inhibitory dietary supplement lead with excellent clinical applications potential. Note: This abstract was not presented at the meeting. Citation Format: Abu Bakar Siddique, Nehad M. Ayoub, Khalid A. El Sayed. Olive oil-derived (-)-oleocanthal for prevention of breast cancer recurrence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4810.

Downregulation of WW domain-containing oxidoreductase leads to tamoxifen-resistance by the inactivation of Hippo signaling.

Acquired tamoxifen-resistance is an important cause of death in patients with hormone-dependent breast tumors. Therefore, understanding the molecular mechanisms underlying the development of tamoxifen-resistance is critical for successful endocrine therapy. This study aimed to define the role of WW domain-containing oxidoreductase (WWOX) in acquired tamoxifen-resistance. Our results show that low WWOX expression was significantly related to tamoxifen-resistance. Moreover, WWOX-knockdown increased resistance to tamoxifen, while WWOX overexpression decreased the resistance. Furthermore, WWOX silencing decreased Yes-associated protein (YAP) phosphorylation and increased YAP nuclear translocation. Finally, YAP silencing decreased tamoxifen-resistance in WWOX-knockdown cells. Our findings demonstrate that WWOX downregulation can lead to the development of tamoxifen-resistance by inactivating Hippo signaling. Thus, WWOX might be a valuable target and prognostic marker for tamoxifen-resistance. Impact statement Understanding the molecular pathways leading to the development of tamoxifen-resistance is an important research focus as acquired tamoxifen-resistance is the main cause of death in patients with benign primary prognosis. Although WW domain-containing oxidoreductase (WWOX) has been related to breast tumorigenesis, its role in acquired tamoxifen-resistance has not yet been demonstrated. Our findings show that WWOX might be a valuable therapeutic target and prognostic marker for tamoxifen-resistance.

Abstract 2733: Novel function of the RAI2 protein in genomic integrity of breast cancer cells

Abstract We have recently identified the RAI2 protein as putative metastasis-suppressor related to dedifferentiation, early occurring bone metastasis formation, and survival of hormone dependent breast carcinomas. Nevertheless, low RAI2 expression is also predictive for poor patient outcome in hormone independent tumors and is furthermore associated with mutation of p53 in primary breast tumors. Thus, besides sustaining luminal differentiation, RAI2 might possess a general function as tumor suppressor that is, as indicated by association with p53 status, possibly related to maintenance of genomic stability. In order to characterize its potential role in genomic integrity, we screened lysates from RAI2 depleted MCF-7 and KPL-1 breast cancer cell lines with phosphorylation-specific antibody arrays. Additionally, we analyzed changes in expression of cell cycle related genes and proteins by qPCR and Western Blot analysis. We also conducted cytogenetic assays to investigate whether RAI2 depletion affects chromosomal stability and mitotic progression. Finally, we evaluated a possible association of RAI2 expression with aneuploidy in published expression data sets from breast cancer patients. As revealed by antibody array analysis, RAI2 depletion causes activation of p53 protein in MCF-7 and KPL-1 breast cancer cells, which was accompanied by a significant increase of senescent cells in the corresponding cell populations. Furthermore RAI2 depletion causes downregulation of several key factors of G2/M transition, like Aurora kinases A and B as well as Cyclins A2, B1 and B2. Concomitantly, we found in RAI2-depleted cell cultures reduction of mitotic index, increase of unattached chromosomes in metaphase and lagging chromosomes and during anaphase. This finding was further approved by an increase of numerical aberrations in RAI2 knockdown cells. Finally, we could show an association between low RAI2 expression and higher level of chromosomal instability in primary tumors from breast cancer patients. In conclusion, we found that loss of RAI2 function is associated with decreased mitotic fidelity. Thus, besides sustaining differentiation in hormone dependent breast tumor, RAI2 also acts as general tumor suppressor that maintains genomic integrity. Reference: Werner S et al., Cancer Discovery. 2015 May;5(5):506-19 Citation Format: Stefan Werner, Kerstin Borgmann, Klaus Pantel, Harriet Wikman. Novel function of the RAI2 protein in genomic integrity of breast cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2733.

Tyrosine phosphorylation regulates ERβ ubiquitination, protein turnover, and inhibition of breast cancer.

Unlike estrogen receptor α (ERα) that predominantly promotes hormone-dependent breast tumor growth, ERβ exhibits antitumor effects in a variety of cancer types. We recently identified a phosphotyrosine residue in ERβ, but not ERα, that dictates ERβ transcriptional activity and antitumor function. We show here that this ER isotype-specific phosphotyrosine switch is important for regulating ERβ activity in cell proliferation, migration, and invasion. At the mechanistic level, phosphorylated ERβ, which recruits transcriptional coactivator p300, is in turn targeted by p300 for ubiquitination and proteasome-dependent protein turnover. Furthermore, ERβ-specific agonists such as S-equol enhance ERβ phosphorylation, suggesting a crosstalk between ligand- and posttranslational modification-dependent ERβ activation. Inhibition of xenograft tumor growth by S-equol is associated with reduced tumor Ki-67 expression and elevated ERβ tyrosine phosphorylation. Taken together, our data support the notion that phosphotyrosine-dependent ERβ signaling is an attractive target for anticancer treatment.

Аліментарні тригери гормонзалежних форм раку молочної залози

Досліджено процеси перекисного окиснення ліпідів і стан системи антиокисного захисту в організмі щурів різного віку, що піддавалися впливу екзоестрогенів. Установлено різний ступінь інтенсифікації пероксидації залежно від віку та дослідного органа: максимальне перевищення контрольних показників відмічене у сироватці крові, що свідчить про вплив синтетичних естрогенів на всі основні системи організму. У самиць у препубертатному періоді у печінці реакція прооксидантної системи та напруження в системі антиоксидантного захисту перевищували силу відповіді в органі статевозрілих тварин. Відмічено органну дискретність змін активності ензимів антиоксидантного захисту, яка залежить від віку тварин. Ураховуючи залучення системи глутатіону до дезактивації естрогенів шляхом їх кон’югації в реакціях, що каталізуються глутатіонтрансферазою, зниження активності ензиму може викликати накопичення високоактивних проміжних метаболітів із наступним пошкодженням внутрішньоклітинних структур. Ці феномени надалі можуть стати тригером зниження потенціалу компенсаторних механізмів, що разом із генотоксичною дією екзоестрогенів є важливою патогенетичною ланкою в канцерогенезі: ініціюють розвиток проліферативних процесів та виникнення в майбутньому ракових станів і, зокрема, гормонзалежних пухлин молочної залози.

Systemic Magnetic Targeting of Pure-Antiestrogen-Loaded Superparamagnetic Nanovesicles for Effective Therapy of Hormone- Dependent Breast Cancers

Systemic hormone therapy of breast cancer often suffers from severe side effects mainly due to non-specific drug delivery. To overcome this limitation, we propose an effective strategy based on the association of the selective estrogen receptor down-regulator RU-58668 (RU) that acts as a pure hormone antagonist, with magnetic-fluidloaded liposomes (MFLs) which can be driven selectively into the tumors by a magnetic field gradient. MFLs consisted in 200-nm unilamellar phospholipid vesicles entrapping superparamagnetic iron oxide nanocrystals, fluorescently labeled and coated by poly(ethylene glycol) (PEG) chains ensuring long plasmatic half-life. Significant antitumoral activity of antiestrogen at doses usually sub-therapeutic was demonstrated against MCF-7 tumors xenografts in nude mice after weekly intravenous administration of RU-loaded MFLs followed by 4-hour exposure to an external 0.44-T magnet (155 T/m magnetic field gradient). The magnetic accumulation of RU-MFLs at the origin of improved antitumor activity was checked in vivo by MRI using the magnetic fluid as intrinsic contrast agent, fibered confocal fluorescence microscopy to track the lipid vesicle structures, ex-vivo tumor histology by confocal fluorescence microscopy or iron oxide staining, and KI-67 immunostaining to reveal RU anti-proliferative activity. Our findings establish that magnetic targeting results in significant therapeutic benefit by highly concentrating RUloaded liposomes in the tumor tissue according to amplified EPR effect and significantly enhanced drug delivery at the intracellular level. The use of superparamagnetic liposomes to target magnetically estrogen antagonists offers a reliable direction to treat hormone-dependent breast tumors with possible combination of MRI diagnosis.

The G protein-coupled receptor GPR30 mediates the proliferative and invasive effects induced by hydroxytamoxifen in endometrial cancer cells

The selective ER modulator tamoxifen (TAM1Abbreviations: GPR30, G protein-coupled receptor 30; E2, 17β-estradiol; MMP, Matrix metal-loproteinase; MAPK, Mitogen-activated protein kinase; TAM, Tamoxifen; OHT, 4-Hydroxytamoxifen; ShGPR30-pGFP-V-RS, Short hairpin RNA (shRNA) constructs against GPR30 in pGFP-V-RS; shiv-pGFP-V-RS vector, HuSH 29-mer noneffective against enhanced GFP vector; EGFR, Epidermal growth factor receptor; ERK, Extracellular-signal-regulated kinase; DMEM, Dulbecco’s modified Eagle’s medium.1) is the most widely used ER antagonist for treatment of women with hormone-dependent breast tumor. However, long-term treatment is associated with an increased risk of endometrial cancer. The aim of the present study was to demonstrate new insight into the role of G-protein coupled receptor 30 (GPR30) in the activity of TAM, which promoted endometrial cancer. In endometrial cancer cell lines ISHIKAWA and KLE, the potential of 4-hydroxytamoxifen (OHT), the active metabolite of TAM, 17β-estradiol (E2) and G1, a non-steroidal GPR30-specific agonist to promote cell proliferation and invasion was evaluated. All agents above induced high proliferative and invasive effects, while the down-regulation of GPR30 or the interruption of MAPK signal pathway partly or completely prevented the action of the regent. Moreover, the RNA and protein expression of GPR30 was up-regulated by G1, E2 or OHT in both cell lines. The present study provided a new insight into the mechanism involved in the agonistic activity exerted by TAM in the uterus.

Biophysical studies of the interaction between calmodulin and the R287-T311 region of human estrogen receptor α reveals an atypical binding process

The transcriptional activity of human estrogen receptor ERα is modulated by a number of coregulatory proteins among which calmodulin (CaM). Segment 295–311 in the hinge region of ERα has previously been proposed to be the CaM binding site. In this work, we investigate the molecular mechanism of the interaction of CaM with peptides derived from the hinge region of ERα, using a biophysical approach combining isothermal titration calorimetry, fluorescence, CD and NMR. The ERα17p peptide, corresponding to the previously identified 295–311 region of ERα, recruits mainly the C-terminal domain of Ca4CaM, as shown by NMR spectroscopy. In contrast, a longer peptide, ERα25p, extended on the N-terminal side (residues 287–311) interacts with both N- and C-terminal domains of Ca4CaM. These results lead to a new delineation of the CaM binding site, encompassing residues 287–294. In particular, fluorescence spectroscopy reveals that the conserved W292 residue is engaged within hydrophobic pockets on Ca4CaM. ITC results show that ERα25p binds Ca4CaM with an atypical 2:1 stoichiometry and a dissociation constant in the micromolar range. Based on the NMR titration of Ca4CaM by ERα25p showing a biphasic behavior for several residues, we suggest that concerted conformational changes of CaM domains may be required to accommodate the binding of a second peptide. CD spectra indicate that ERα25p partially folds into an α-helix upon binding to Ca4CaM. Hence, ERα25p is a new CaM-binding ligand that could be appropriate for the synthesis of derivatives able to control ER-dependent transcription, particularly in the context of hormone-dependent breast tumors.

Anti-hormones: Mechanism and Use in Treatment of Breast Cancer

Breast cancer is the second-leading cause of cancer-related death in women. Recently, new drugs are being developed based on the molecular mechanisms of receptors, tumor suppressor genes, monoclonal antibodies, tumor markers and antihormone therapy. Anti-hormone therapy is used in the treatment of hormone-dependent breast tumors. Among the anti-hormone therapies, a substantial amount of research has been focused on the development of the ideal selective estrogen receptor modulator to treat metastatic breast tumors and to prevent breast cancer in high risk women.

Cell proliferation regulated by estradiol receptor: Therapeutic implications

Estrogen receptor (ER) is a ligand-regulated transcription factor that controls human breast cancer cell proliferation. About 60–70% of human breast cancers express ER. In spite of major progress in the therapy of human breast cancer, many patients become resistant to pharmacologic treatments and develop metastatic breast tumors. Several mechanisms have been proposed to explain tumor progression and resistance to the therapies. However, the causes of hormone-dependent breast tumor progression as well as therapy resistance are still debated. An increasing body of evidence from our and other laboratories shows that in breast cancer cells, in addition to its classical transcriptional action, ER stimulates proliferative and anti-apoptotic signaling pathways in response to either ligand binding or growth factors. This discovery has led to the synthesis of new compounds specifically interfering in the rapid responses mediated by ER. It also suggests that the modalities currently in use for breast cancer treatment need to be reconsidered.

Primary hormonal therapy with exemestane in patients with breast tumors >3 cm in diameter: Results of a Spanish multicenter phase II trial

603 Background: Primary hormonal therapies have demonstrated great activity in elderly women with locally advanced and hormone-dependent breast tumors. Exemestane, a steroidal aromatase inactivator, is effective in a metastatic setting. The primary aim of this study was to analyze the efficacy of exemestane as a neoadjuvant treatment. Methods: 55 patients (p) were recruited. Inclusion criteria were histologic diagnosis of infiltrating breast carcinoma, no metastatic disease, tumor >3 cm (T2, T3, T4a-b), >50% ER+, and no previous hormonal treatment/chemotherapy. At baseline, all p were considered noneligible for breast-conserving surgery. Treatment: oral exemestane 25 mg/d for 6 months. Response was estimated by mammography and breast ultrasound every 2 months (RECIST criteria). Secondary endpoints were rate of breast-conserving surgery, time to progression, duration of response, and toxicity. To date, 50 p have been evaluated for response and 5 remain under treatment. Results: Patient characteristics: med...

Primary hormonal therapy with exemestane in patients with breast tumors >3 cm in diameter: Results of a Spanish multicenter phase II trial

603 Background: Primary hormonal therapies have demonstrated great activity in elderly women with locally advanced and hormone-dependent breast tumors. Exemestane, a steroidal aromatase inactivator, is effective in a metastatic setting. The primary aim of this study was to analyze the efficacy of exemestane as a neoadjuvant treatment. Methods: 55 patients (p) were recruited. Inclusion criteria were histologic diagnosis of infiltrating breast carcinoma, no metastatic disease, tumor >3 cm (T2, T3, T4a-b), >50% ER+, and no previous hormonal treatment/chemotherapy. At baseline, all p were considered noneligible for breast-conserving surgery. Treatment: oral exemestane 25 mg/d for 6 months. Response was estimated by mammography and breast ultrasound every 2 months (RECIST criteria). Secondary endpoints were rate of breast-conserving surgery, time to progression, duration of response, and toxicity. To date, 50 p have been evaluated for response and 5 remain under treatment. Results: Patient characteristics: med...

Differentially expressed genes and estrogen receptor status in breast cancer

There is a large and increasing body of experimental and clinical data supporting the involvement of estrogen on the proliferation of hormone-dependent breast tumors. Estrogen acts via its receptor (ER) stimulating cellular proliferation. ER and progesterone receptor (PR), which is regulated by estrogen via ER, have been used as prognostic markers in the clinical management of breast cancer patients. The aim of the present study was the identification of tumor-associated genes differentially expressed in breast tumors regarding the presence or absence of ER and PR. Using the technique of differential display reverse transcriptase-polymerase chain reaction (DDRT-PCR) we have isolated and cloned 127 cDNA fragments that showed differential expression in either ER+/PR+ or ER-/PR- breast tumors. Sequencing analysis of these clones revealed that 119 cDNAs had homology with known sequences in the National Center of Biotechnology Information (NCBI) and 8 were novel, showing no homology to known genes. Among these differentially expressed transcripts are metabolic enzymes, ribosomal proteins, transcription factors, hypothetical proteins, cell cycle regulators, cytoskelectum related genes, cell adhesion and motility genes. Differences in gene expression profiles are likely to explain the phenotypic differences between hormone-responsive and hormone-unresponsive breast tumors.

Aromatase overexpression enhances the stimulatory effects of adrenal androgens on MCF7 breast cancer cells

The intratumoral conversion of adrenal androgens into estrogens by the aromatase enzyme complex may be an important mechanism of autocrine stimulation in hormone-dependent breast tumor. The effects of estrogens on tumor development are mediated by the activity of estrogen receptor α that induces gene expression and cell proliferation. Thus, estrogen biosynthesis ‘in situ’ and/or estrogen receptor action are the main targets of endocrine treatment in endocrine-dependent breast carcinoma. In the present study we demonstrate that three major adrenal androgens, dehydroepiandrosterone, 5-androstene-3β, 17β-diol and 4-androstene 3,17-dione, all acquire an estradiol-like biological efficacy in aromatase transfected MCF7 breast cancer cells. Our results suggest that in postmenopausal women aromatase inhibitors might be considered as an adjuvant approach to the treatment of hormone-dependent breast tumors that overexpress aromatase.

The direct proliferative stimulus of dehydroepiandrosterone on MCF7 breast cancer cells is potentiated by overexpression of aromatase

In women after menopause aromatization of adrenal androgens represents the main source of estrogens, which may promote the development of hormone-dependent breast tumor. Several studies have attempted to determine the cell type within carcinomas that is responsible for ‘in situ’ estrogen biosynthesis and whether the amount produced may sustain relevant biological effects. Here we show P450arom mRNA and protein expression together with immunocytochemical localization of aromatase in the epithelial MCF7 breast cancer cell line. Moreover, we demonstrate that the enhanced aromatization of dehydroepiandrosterone in aromatase transfected MCF7 cells confers biological advantages such as proliferative stimulation similar to that induced by estradiol. Our results suggest that aromatase inhibitors may be particularly effective in the treatment of hormone-dependent breast cancer disease in postmenopausal women.