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OBJECTIVE: Obesity adversely impacts breast cancer treatment and outcomes. This study assessed the efficacy of nurses' motivational interviews (MI) in promoting weight loss among breast cancer patients. METHODS: Motivational Interviewing was performed at 4, 8, and 12 weeks from baseline in 27 overweight/ obese breast cancer patients receiving adjuvant endocrine therapy. An average weight loss rate of 5% at week 12 was the threshold for determining whether MI intervention was clinically meaningful. Clinical and sociodemographic variables were gathered from medical records and self-administered questionnaires. Body weight, body mass index (BMI), physical activity time, sedentary time, self-efficacy for weight loss, and mood scores were evaluated at baseline, 4, 8, 12, and 24 weeks. RESULTS: Significant reductions in body weight were observed throughout compared with baseline; 51.9% of participants attained the 5% weight loss target, but the average weight loss rate was 3.9% at week 12. BMI notably decreased at 8, 12, and 24 weeks compared with baseline. Physical activity increased significantly at 12 weeks, while sedentary time decreased at 8 and 24 weeks. CONCLUSIONS: Nursing-administered MI did not achieve the goal of 5% weight loss at week 12. However, it increased physical activity and reduced sedentary time, showing potential for promoting healthier habits.
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Neoplasias de la Mama , Entrevista Motivacional , Humanos , Femenino , Sobrepeso/complicaciones , Sobrepeso/terapia , Neoplasias de la Mama/terapia , Obesidad/complicaciones , Obesidad/terapia , Peso Corporal , Pérdida de PesoRESUMEN
BACKGROUND: Alpha-2-glycoprotein 1, zinc-binding (ZAG), a secreted protein encoded by the AZGP1 gene, is structurally similar to HLA class I. Despite its presumed immunological function, little is known about its role in tumor immunity. In this study, we thus aimed to determine the relationship between the expression of AZGP1/ZAG and the immunological profiles of breast cancer tissues at both the gene and protein level. METHODS: Using a publicly available gene expression dataset from a large-scale breast cancer cohort, we conducted gene set enrichment analysis (GSEA) to screen the biological processes associated with AZGP1. We analyzed the correlation between AZGP1 expression and immune cell composition in breast cancer tissues, estimated using CIBERSORTx. Previously, we evaluated the infiltration of 11 types of immune cells for 45 breast cancer tissues using flow cytometry (FCM). ZAG expression was evaluated by immunohistochemistry on these specimens and analyzed for its relationship with immune cell infiltration. The action of ZAG in M1/M2 polarization models using primary cultures of human peripheral blood mononuclear cells (PBMC)-derived macrophage (Mφ) was analyzed based on the expression of M1/M2 markers (CD86, CD80/CD163, MRC1) and HLA class I/II by FCM. RESULTS: AZGP1 expression was negatively correlated with multiple immunological processes and specific immune cell infiltration including Mφ M1 using GSEA and CIBERSORTx. ZAG expression was associated with decreased infiltration of monocytes/macrophages, non-classical monocytes, and myeloid-derived suppressor cells in tumor tissues assessed using FCM. In in vitro analyses, ZAG decreased the expression of CD80, CD163, MRC1, and HLA classes I/II in the M1 polarization model and the expression of CD163 and MRC1 in the M2 polarization model. CONCLUSION: ZAG is suggested to be a novel immunoregulatory factor affecting the Mφ phenotype in breast cancer tissues.
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Neoplasias de la Mama , Femenino , Humanos , Antígeno B7-1 , Glicoproteínas , Leucocitos Mononucleares , Microambiente Tumoral , ZincRESUMEN
Ataxia telangiectasia (AT) is a rare autosomal recessive disorder caused by the pathological variants of the ATM gene. Owing to i ts r arity a nd n ature, complications of AT, such a s malignant tumors, a re often difficult to manage with standard imaging studies and treatments, and there are no established management strategies. We report the case of a woman who had AT in childhood and developed breast cancer in her 20s; the disease was successfully managed by the decision-making of multidisciplinary physicians professionals with ethics support. She was immunocompromised, ataxic, and mentally impaired. The patient's mother noticed a tumor in her right breast and subsequently brought her to our department. Although preoperative testing and surgical procedures were limited as AT is extremely radiosensitive, the patient was diagnosed with cT2N0M0 breast cancer and underwent right mastectomy and axillary lymph node sampling. The final diagnosis was pT2N0M0 pStage IIA mucinous carcinoma, and immunohistochemistry of the tumor specimen was estrogen receptor-positive, progesterone receptor-positive, and HER2-negative. Tamoxifen was administered as postoperative adjuvant therapy, and the patient has survived to date without recurrence. Here, we report our experience with breast cancer treatment for AT, along with a review of the literature.
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Ataxia Telangiectasia , Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/complicaciones , Neoplasias de la Mama/terapia , Mastectomía , Tamoxifeno , Terapia CombinadaRESUMEN
BACKGROUND: Elucidating the unique immunoregulatory mechanisms in breast cancer microenvironment may help develop new therapeutic strategies. Some studies have suggested that hormone receptors also have immune regulatory functions, but their mechanisms are not fully understood. In this study, we have comprehensively analyzed the relationship between the expressions of estrogen (ER), progesterone (PgR), and androgen receptors (AR), and the immunological profile in breast cancer. METHODS: Using publicly available gene expression profile datasets, METABRIC and SCAN-B, the associations between the expressions of hormone receptors and the immune cell compositions in breast cancer tissue, estimated by CIBERSORTx algorithm, were analyzed. We histologically evaluated tumor-infiltrating lymphocytes (hTIL), PD-L1 (hPD-L1) expression, and the infiltration of 11 types of immune cells by flow cytometry (FCM) for 45 breast cancer tissue samples. The relationships between them and the expressions of ER, PgR, and AR of tumor tissues, evaluated immunohistochemically, were analyzed. RESULTS: Expressions of ESR1, PGR, and AR were negatively correlated with overall immune composition. Expressions of ER and AR, but not that of PgR, were inversely associated with hTIL and hPD-L1 expression. FCM analysis showed that the expressions of ER and AR, but not that of PgR, were associated with decreased total leukocyte infiltration. Both CIBERSORTx and FCM analysis showed that ER expression was associated with reduced infiltration of macrophages and CD4+ T cells and that of AR with reduced macrophage infiltration. CONCLUSION: Hormone receptor expression correlates with specific immunological profiles in the breast cancer microenvironment both at the gene and protein expression levels.
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Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/genética , Microambiente Tumoral/genética , Mama , Estrógenos , AlgoritmosRESUMEN
Breast cancer is one of the most common malignancies in women worldwide. Although most breast cancers are curable, in cases of metastasis, many are often found in the lungs, bones, liver, and central nervous system; however, metastasis to the gastrointestinal tract is rare. Invasive lobular carcinoma, which represents only 5%-10% of breast cancers, has a higher risk of metastasis to the gastrointestinal tract than invasive ductal carcinoma. Here, we report a rare case of gastrointestinal metastasis of invasive lobular carcinoma that spread extensively to the colonic mucosa. Given the improved survival rates of breast cancer patients with current treatments, many rarer metastatic diseases, including gastrointestinal metastases, are likely to be increased in the future.
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PURPOSE: Male breast cancer (MBC) is a rare cancer accounting for only 1% of all male cancers and is, therefore, poorly studied. We aimed to characterize the subtypes of MBC in Japanese patients based on genetic profiling, the presence of tumor-infiltrating cells, and the expression of immunohistochemical markers. METHODS: This retrospective study included 103 patients with MBC diagnosed between January 2009 and December 2019 at various hospitals in Japan. Clinicopathological patient characteristics were obtained from medical records, and formalin-fixed paraffin-embedded tissue specimens were analyzed for histological markers, mutations of 126 genes, BRCA1 methylation, and stromal tumor-infiltrating lymphocytes. RESULTS: The median patient age was 71 (range 31-92) years. T1-stage tumors were the most frequent (47.6%), and most were node negative (77.7%). The majority of tumors were positive for estrogen receptor (98.1%), progesterone receptor (95.1%), and androgen receptor (96.1%), and BRCA2 was the most frequently mutated gene (12.6%). The most common treatment was surgery (99.0%), either total mastectomy (91.1%) or partial mastectomy (7.0%). Survival analysis showed a 5-year recurrence-free survival rate of 64.4% (95% confidence interval [CI] 46.7-88.8) and a 5-year overall survival rate of 54.3% (95% CI 24.1-100.0). CONCLUSION: Japanese MBC is characterized by a high rate of hormonal receptor positivity and BRCA2 somatic mutation. Due to the observed clinicopathological differences in MBC between the Western countries and Japan, further prospective studies are needed to evaluate the most suitable treatment strategies.
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Neoplasias de la Mama Masculina , Neoplasias de la Mama , Adulto , Anciano , Anciano de 80 o más Años , Humanos , Masculino , Persona de Mediana Edad , Proteína BRCA1/genética , Proteína BRCA1/metabolismo , Neoplasias de la Mama/patología , Neoplasias de la Mama Masculina/patología , Pueblos del Este de Asia , Mastectomía , Metilación , Mutación , Estudios RetrospectivosRESUMEN
Tumor-infiltrating lymphocytes (TILs) and programmed cell death 1 ligand 1 (PD-L1) are established prognostic and predictive biomarkers for certain breast cancer subsets. However, their association with the immune response complexity is not fully understood. Therefore, we analyzed the association between the immune cell fractions in breast cancer tissues and histologically assessed TIL (hTIL) and PD-L1 (hPD-L1). Forty-five tumor and eighteen blood samples were collected from patients with breast cancer. Total leukocyte counts, frequency of 11 immune cell populations, and PD-L1 expression in each cell fraction were evaluated by flow cytometry. TILs and PD-L1 were assessed by hematoxylin and eosin staining and immunohistochemistry, respectively. A higher hTIL score showed association with increased leukocyte infiltration, higher CD4+ and CD8+ T cell proportions, and lower natural killer and natural killer T cell proportions. PD-L1 was highly expressed in nonclassical monocytes, monocyte/macrophages, myeloid-derived suppressor cells, myeloid dendritic cells, dendritic cells, and other lineages in tumors. hPD-L1 positivity reflected PD-L1 expression accurately in these fractions, as well as increased leukocyte infiltration in tumors. These results indicate that hTILs reflect differences in the immune responses in the tumor microenvironment, and certain immune cell fractions are favorably expressed in the PD-L1 pathway in breast cancer microenvironments.
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Antígeno B7-H1 , Neoplasias de la Mama , Linfocitos Infiltrantes de Tumor , Microambiente Tumoral , Antígeno B7-H1/metabolismo , Mama/patología , Neoplasias de la Mama/patología , Linfocitos T CD8-positivos , Femenino , Humanos , Pronóstico , Microambiente Tumoral/inmunologíaRESUMEN
BACKGROUND/AIM: Carboxyl terminus of Hsc70-interacting protein (CHIP) is a ubiquitin ligase that induces ubiquitination and degradation of its target proteins including oncoproteins. We reported that its down-regulation is associated with tumor progression and metastasis of breast cancer. However, the mechanism through which CHIP gene affects cancer cells is unclear. MATERIALS AND METHODS: We extracted RNA from 45 primary breast cancer samples and compared CHIP mRNA expression profiles, promoter DNA methylation status, and clinicopathological information. RESULTS: CHIP mRNA expression was significantly correlated with the tumor progression status. In several samples, a pinpoint CpG methylation in the CHIP gene promoter region was significantly correlated with CHIP mRNA expression. When this specific CpG was methylated in estrogen receptor (ER)-positive cases, a significant difference in 5-year recurrence was not found compared with ER-negative cases. CONCLUSION: CpG methylation contributes to the long-term prognosis of ER-positive breast cancer.
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Neoplasias de la Mama/genética , Ubiquitina-Proteína Ligasas/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Islas de CpG , Metilación de ADN , Progresión de la Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Pronóstico , Regiones Promotoras Genéticas , ARN Mensajero/genética , Receptores de Estrógenos/metabolismo , Recurrencia , Células Tumorales CultivadasRESUMEN
PURPOSE: Accumulating evidence has attracted attention to the androgen receptor (AR) as a biomarker and therapeutic target in breast cancer. We hypothesized that AR activity within the tumor has clinical implications and investigated whether androgen responsive serum factors might serve as a minimally invasive indicator of tumor AR activity. METHODS: Based on a comprehensive gene expression analysis of an AR-positive, triple negative breast cancer patient-derived xenograft (PDX) model, 163 dihydrotestosterone (DHT)-responsive genes were defined as an androgen responsive gene set. Among them, we focused on genes that were DHT-responsive that encode secreted proteins, namely KLK3, AZGP1 and PIP, that encode the secreted factors prostate specific antigen (PSA), zinc-alpha-2-glycoprotein (ZAG) and prolactin induced protein (PIP), respectively. Using AR-positive breast cancer cell lines representing all breast cancer subtypes, expression of candidate factors was assessed in response to agonist DHT and antagonist enzalutamide. Gene set enrichment analysis (GSEA) was performed on publically available gene expression datasets from breast cancer patients to analyze the relationship between genes encoding the secreted factors and other androgen responsive gene sets in each breast cancer subtype. RESULTS: Anti-androgen treatment decreased proliferation in all cell lines tested representing various tumor subtypes. Expression of the secreted factors was regulated by AR activation in the majority of breast cancer cell lines. In GSEA, the candidate genes were positively correlated with an androgen responsive gene set across breast cancer subtypes. CONCLUSION: KLK3, AZGP1 and PIP are AR regulated and reflect tumor AR activity. Further investigations are needed to examine the potential efficacy of these factors as serum biomarkers.
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Adipoquinas/metabolismo , Neoplasias de la Mama/metabolismo , Calicreínas/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Antígeno Prostático Específico/metabolismo , Receptores Androgénicos/metabolismo , Adipoquinas/genética , Antagonistas de Receptores Androgénicos/farmacología , Andrógenos/farmacología , Animales , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Calicreínas/genética , Masculino , Proteínas de Transporte de Membrana/genética , Ratones , Antígeno Prostático Específico/genética , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Mutations in ESR1 that confer constitutive estrogen receptor alpha (ER) activity in the absence of ligand are acquired by ≥40% of metastatic breast cancers (MBC) resistant to adjuvant aromatase inhibitor (AI) therapy. To identify targetable vulnerabilities in MBC, we examined steroid hormone receptors and tumor-infiltrating immune cells in metastatic lesions with or without ER mutations. ER and progesterone receptor (PR) were significantly lower in metastases with wild-type (WT) ER compared with those with mutant ER, suggesting that metastases that evade AI therapy by mechanism(s) other than acquiring ER mutations lose dependency on ER and PR. Metastases with mutant ER had significantly higher T regulatory and Th cells, total macrophages, and programmed death ligand-1 (PD-L1)-positive immune-suppressive macrophages than those with WT ER. Breast cancer cells with CRISPR-Cas9-edited ER (D538G, Y537S, or WT) and patient-derived xenografts harboring mutant or WT ER revealed genes and proteins elevated in mutant ER cells, including androgen receptor (AR), chitinase-3-like protein 1 (CHI3L1), and IFN-stimulated genes (ISG). Targeting these proteins blunted the selective advantage of ER-mutant tumor cells to survive estrogen deprivation, anchorage independence, and invasion. Thus, patients with mutant ER MBC might respond to standard-of-care fulvestrant or other selective ER degraders when combined with AR or CHI3L1 inhibition, perhaps with the addition of immunotherapy. SIGNIFICANCE: Targetable alterations in MBC, including AR, CHI3L1, and ISG, arise following estrogen-deprivation, and ER-mutant metastases may respond to immunotherapies due to elevated PD-L1+ macrophages.See related article by Arnesen et al., p. 539.
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Neoplasias de la Mama , Receptor alfa de Estrógeno , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Receptor alfa de Estrógeno/genética , Fulvestrant/farmacología , Expresión Génica , Humanos , MutaciónRESUMEN
Triple-negative breast cancer (TNBC) is an aggressive subtype with peak recurrence as metastatic disease within the first few years of diagnosis. Androgen receptor (AR) expression is increased in anchorage-independent cells in TNBC preclinical models. Both AR knockdown and inhibition lead to reduced TNBC invasion in vitro, reduced tumorigenicity, and less recurrence in vivo in preclinical models. Transforming growth factor ß (TGFß) pathway gene signatures also increased during anchorage-independent survival both in vitro and in vivo in preclinical models and in circulating tumor cells (CTCs) from patients during emergence of chemo resistant disease. We hypothesized that a positive loop between AR and TGFß signaling facilitates TNBC anchorage-independent survival. We find that multiple components of the TGFß pathway, including TGFß1 and 3, as well as pathway activity measured by nuclear localization and transcriptional activity of phosphorylated Smad3, are enhanced in anchorage-independent conditions. Further, exogenous TGFß increased AR protein while TGFß inhibition decreased AR and TNBC viability, particularly under anchorage-independent culture conditions. ChIP-seq experiments revealed AR binding to TGFB1 and SMAD3 regulatory regions in MDA-MB-453 cells. In clinical datasets, TGFB3 and AR positively correlate and high expression of both genes together corresponded to significantly worse recurrence-free and overall survival in both ER-negative and basal-like breast cancer. Finally, inhibiting both AR and TGFß decreased cell survival, particularly under anchorage-independent conditions. These findings warrant further investigations into whether combined inhibition of AR and TGFß pathways might decrease metastatic recurrence rates and mortality from TNBC.
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Anoicis , Recurrencia Local de Neoplasia/etiología , Receptores Androgénicos/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Neoplasias de la Mama Triple Negativas/metabolismo , Línea Celular Tumoral , Retroalimentación Fisiológica , Humanos , Neoplasias de la Mama Triple Negativas/mortalidadRESUMEN
BACKGROUND: Recent preclinical data suggest that androgen receptor (AR) signaling plays a significant role in subsets of breast cancer. Clinical trials testing AR-targeting therapies in breast cancer have been conducted. Assessment of AR-signal in breast cancer tissue maybe useful for treatment selections. Prostate specific antigen (PSA) is the product of an androgen-responsive gene. Serum PSA (sPSA) can be detected in women by a highly sensitive assay although the concentration is much lower than that observed in males. We investigated if sPSA reflects tumor biology, including AR signaling in breast cancer patients. METHODS: In this study, 132 healthy controls and 144 breast cancer patients were enrolled. sPSA was evaluated by the chemiluminescent enzyme immunoassay (CLEIA) method. Correlations between sPSA and the various clinicopathological factors were analyzed. RESULTS: In post-menopausal state, sPSA detection rate was significantly higher in breast cancer patients compared with controls (27.4% vs 11.3%: p = 0.0090), but not in the whole cohort (29.2% vs 25.8%: p = 0.5265) or pre-menopausal subgroup (37.0% vs 42.6%: p = 0.6231). In post-menopausal breast cancer cases, higher sPSA value was associated with clinic-pathological factors including the expression of AR protein in primary legion. In a correlation analysis of quantitative data limited to post-menopausal metastatic breast cancer (MBC), sPSA was positively, albeit weakly correlated with clinic-pathological features including serum testosterone levels and AR positivity. CONCLUSIONS: Our data suggest that sPSA may reflect tumor biological properties including AR activity in post-menopausal breast cancer.
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Neoplasias de la Mama/sangre , Neoplasias de la Mama/patología , Calicreínas/sangre , Antígeno Prostático Específico/sangre , Adulto , Anciano , Antineoplásicos Hormonales/uso terapéutico , Biomarcadores de Tumor/sangre , Neoplasias de la Mama/tratamiento farmacológico , Estudios de Cohortes , Femenino , Humanos , Técnicas para Inmunoenzimas/métodos , Persona de Mediana Edad , Posmenopausia/sangre , Receptores Androgénicos/metabolismo , Testosterona/sangreRESUMEN
We previously reported the establishment of several types of long-term estrogen-depleted-resistant (EDR) cell lines from MCF-7 breast cancer cells. Type 1 EDR cells exhibited the best-studied mechanism of aromatase inhibitor (AI) resistance, in which estrogen receptor (ER) expression remained positive and PI3K signaling was upregulated. Type 2 EDR cells showed reduced ER activity and upregulated JNK-related signaling. The mTOR inhibitor everolimus reduced growth in cells similar to Type 1 EDR cells. The present study generated everolimus-resistant (EvR) cells from Types 1 and 2 EDR cells following long-term exposure to everolimus in vitro. These EvR cells modeled resistance to AI and everolimus combination therapies following first-line AI treatment failure. In Type 1 EvR cells, everolimus resistance was dependent on MAPK signaling; single agents were not effective, but hormonal therapy combined with a kinase inhibitor effectively reduced cell growth. In Type 2 EvR cells, ER expression remained negative and a JNK inhibitor was ineffective, but a Src inhibitor reduced cell growth. The mechanism of acquired everolimus resistance appears to vary depending on the mechanism of AI resistance. Strategies targeting resistant tumors should be tailored based on the resistance mechanisms, as these mechanisms impact therapeutic efficacy.
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Estrogen plays crucial roles in the progression of hormone-dependent breast cancers through activation of nuclear estrogen receptor α (ER). Estrogen is produced locally from circulating inactive steroids and adrenal androgens in postmenopausal women. However, conversion by aromatase is a rate-limiting step in intratumoral estrogen production in breast cancer. Aromatase inhibitors (AIs) inhibit the growth of hormone-dependent breast cancers by blocking the conversion of adrenal androgens to estrogen and by unmasking the inhibitory effect of androgens, acting via the androgen receptor (AR). AIs are thus a standard treatment option for postmenopausal hormone-dependent breast cancer. However, although initial use of AIs provides substantial clinical benefit, some breast cancer patients relapse because of the acquisition of AI resistance. A better understanding of the mechanisms of AI resistance may contribute to the development of new therapeutic strategies and aid in the search for new therapeutic targets and agents. We have investigated AI-resistance mechanisms and established six AI-resistant cell lines. Some of them exhibit estrogen depletion-resistance properties via constitutive ER-activation or ER-independent growth signaling. We examined how breast cancer cells can adapt to estrogen depletion and androgen superabundance. Estrogen and estrogenic androgen produced independently from aromatase contributed to cell proliferation in some of these cell lines, while another showed AR-dependent cell proliferation. Based on these findings, currently proposed AI-resistance mechanisms include an aromatase-independent estrogen-producing pathway, estrogen-independent ER function, and ER-independent growth signaling. This review summarizes several hypotheses of AI-resistance mechanisms and discusses how existing or novel therapeutic agents may be applied to treat AI-resistant breast cancers.
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Inhibidores de la Aromatasa/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Resistencia a Antineoplásicos/efectos de los fármacos , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Quinasa 4 Dependiente de la Ciclina/metabolismo , Femenino , Humanos , Posmenopausia , Receptores Androgénicos/metabolismo , Receptores de Estrógenos/metabolismoAsunto(s)
Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/patología , Quilo , Escisión del Ganglio Linfático/efectos adversos , Complicaciones Posoperatorias/etiología , Anciano , Neoplasias de la Mama/cirugía , Carcinoma Ductal de Mama/cirugía , Drenaje , Femenino , Humanos , Escisión del Ganglio Linfático/métodos , Ganglios Linfáticos/patología , Ganglios Linfáticos/cirugía , Masculino , Mastectomía , Persona de Mediana Edad , Cuidados Posoperatorios , Complicaciones Posoperatorias/terapiaRESUMEN
Approximately 70% of breast cancers express estrogen receptor α (ERα), which plays critical roles in breast cancer development. Fulvestrant has been effectively used to treat ERα-positive breast cancer, although resistance remains a critical problem. To elucidate the mechanism of resistance to fulvestrant, we established fulvestrant-resistant cell-lines named MFR (MCF-7 derived fulvestrant resistance) and TFR (T-47D derived fulvestrant resistance) from the ERα-positive luminal breast cancer cell lines MCF-7 and T-47D, respectively. Both fulvestrant-resistant cell lines lost sensitivity to estrogen and anti-estrogens. We observed diminished ERα expression at both the protein and mRNA levels. To address the mechanism of gene expression regulation, we examined epigenetic alteration, especially the DNA methylation level of ERα gene promoters. MFR cells displayed high methylation levels upstream of the ERα gene, whereas no change in DNA methylation was observed in TFR cells. Hence, we examined the gene expression plasticity of ERα, as there are differences in its reversibility following fulvestrant withdrawal. ERα gene expression was not restored in MFR cells, and alternative intracellular phosphorylation signals were activated. By contrast, TFR cells exhibited plasticity of ERα gene expression and ERα-dependent growth; moreover, these cells were resensitized to estrogen and anti-estrogens. The difference in epigenetic regulation among individual cells might explain the difference in the plasticity of ERα expression. We also identified an MFR cell-activating HER/Src-Akt/MAPK pathway; thus, the specific inhibitors effectively blocked MFR cell growth. This finding implies the presence of multiple fulvestrant resistance mechanisms and suggests that the optimal therapies differ among individual tumors as a result of differing epigenetic mechanisms regulating ERα gene expression.
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Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Resistencia a Antineoplásicos , Epigénesis Genética/efectos de los fármacos , Estradiol/análogos & derivados , Receptor alfa de Estrógeno/metabolismo , Línea Celular Tumoral , Proliferación Celular , Metilación de ADN , Relación Dosis-Respuesta a Droga , Estradiol/farmacología , Estrógenos/farmacología , Femenino , Fulvestrant , Regulación Neoplásica de la Expresión Génica , Humanos , Sistema de Señalización de MAP Quinasas , Células MCF-7 , Regiones Promotoras Genéticas , Transducción de SeñalRESUMEN
Active sex steroids including estrogens and androgens are locally produced from circulating inactive steroids by various steroid-metabolizing enzymes, and play pivotal roles in the progression of hormone-dependent breast cancers. Human 3ß-hydroxysteroid dehydrogenase type 1 (3ß-HSD type 1) is a critical enzyme in the formation of all classes of active steroid hormones, and is also involved in the inactivation of potent androgen dihydrotestosterone (DHT). Therefore, this enzyme is suggested to modulate active sex steroid production or inactivation, with a role in hormone-dependent breast cancer. The purpose of this study was to investigate the clinical significance of 3ß-HSD type 1 in human breast cancer. Using immunohistochemistry (IHC), we evaluated 3ß-HSD type 1 expression in 161 human breast cancers and analyzed correlations of 3ß-HSD type 1 expression with various clinicopathological factors. Of 161 breast cancer cases, 3ß-HSD type 1 expression in cancer cells was detected in 119 cases (73.9%), and was positively correlated with estrogen receptor (ER)-positivity but not HER-2 status. In ER-positive cases (n = 130), 3ß-HSD type 1 expression was inversely correlated with invasive tumor size (P = 0.0009), presence of invasive region (P = 0.0107), and lymphatic involvement (P = 0.0004). 3ß-HSD type 1 expression was significantly associated with decreased risk of recurrence or improved prognosis by both univariate (P = 0.0003 and P = 0.009, respectively) and multivariate (P = 0.027 and P = 0.023, respectively) analyses. Our findings indicate that this enzyme is a prognostic factor in hormone-dependent breast cancer.
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3-Hidroxiesteroide Deshidrogenasas/metabolismo , Biomarcadores de Tumor , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/mortalidad , 3-Hidroxiesteroide Deshidrogenasas/genética , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/diagnóstico , Femenino , Expresión Génica , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Clasificación del Tumor , Metástasis de la Neoplasia , Estadificación de Neoplasias , Pronóstico , Receptores de Estrógenos/metabolismo , Análisis de Supervivencia , Carga TumoralRESUMEN
Aromatase inhibitors (AIs) effectively treat hormone receptor-positive postmenopausal breast cancer, but some patients do not respond to treatment or experience recurrence. Mechanisms of AI resistance include ligand-independent activation of the estrogen receptor (ER) and signaling via other growth factor receptors; however, these do not account for all forms of resistance. Here we present an alternative mechanism of AI resistance. We ectopically expressed aromatase in MCF-7 cells expressing green fluorescent protein as an index of ER activity. Aromatase-overexpressing MCF-7 cells were cultured in estrogen-depleted medium supplemented with testosterone and the AI, letrozole, to establish letrozole-resistant (LR) cell lines. Compared with parental cells, LR cells had higher mRNA levels of steroid sulfatase (STS), which converts estrone sulfate (E1S) to estrone, and the organic anion transporter peptides (OATPs), which mediate the uptake of E1S into cells. LR cells proliferated more in E1S-supplemented medium than did parental cells, and LR proliferation was effectively inhibited by an STS inhibitor in combination with letrozole and by ER-targeting drugs. Analysis of ER-positive primary breast cancer tissues showed a significant correlation between the increases in the mRNA levels of STS and the OATPs in the LR cell lines, which supports the validity of this AI-resistant model. This is the first study to demonstrate the contribution of STS and OATPs in E1S metabolism to the proliferation of AI-resistant breast cancer cells. We suggest that E1S metabolism represents a new target in AI-resistant breast cancer treatment.
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Inhibidores de la Aromatasa/farmacología , Neoplasias de la Mama/patología , Proliferación Celular/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Receptores de Estrógenos/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Femenino , Humanos , Células Tumorales CultivadasRESUMEN
Lipid-rich carcinoma (LRC) of the breast is a rare breast cancer variant that accounts for <1% of all breast malignancies. It has been reported that LRCs are negative for estrogen receptor. Here, we report a case of LRC of the breast that was strongly positive for estrogen receptor and treated with endocrine adjuvant therapy. A 52-year-old postmenopausal female noticed a lump in her right breast by self-examination and presented to our hospital. Physical examination revealed an elastic 30 mm ×20 mm hard mass in the upper medial part of her right breast. The findings obtained using ultrasonography, mammography, and contrast-enhanced magnetic resonance imaging suggested breast cancer. Core needle biopsy resulted in the diagnosis of invasive carcinoma. The patient underwent mastectomy and sentinel lymph node biopsy. Histopathologically, the tumor cells were abundant in foamy cytoplasm. Because the presence of marked cytoplasmic lipid droplets was confirmed by Sudan IV staining and electron microscopic examination of the tumor and the lipid droplets were negative for periodic acid-Schiff staining, the tumor was diagnosed as an LRC. Immunohistochemically, estrogen and progesterone receptors of the tumor were strongly positive, human epidermal growth factor receptor type 2 was negative, and the ratio of Ki-67-positive cells was ~30%. After surgery, the patient underwent combination chemotherapy with anthracycline, cyclophosphamide, and 5-fluorouracil, followed by docetaxel. Thereafter, the pateint was treated with letrozole and has remained well for 24 months with no signs of recurrence.