Effect of eribulin on epithelial-mesenchymal transition plasticity in metastatic breast cancer: An exploratory, prospective study.

Epithelial-mesenchymal transition (EMT) plays a pivotal role in cancer metastasis and treatment resistance, which worsens prognosis. In phase III trials, eribulin improved overall survival in metastatic breast cancer (MBC) patients. In preclinical studies, eribulin suppressed EMT. However, clinical data on the use of eribulin for MBC patients are limited. In this exploratory, prospective study, we examined the effect of eribulin on EMT in MBC patients. Twenty-two patients aged 44-82 years with recurrent breast cancer or MBC were treated with eribulin. Breast cancer tissue samples were obtained before treatment and on Day 15 ± 5 of the first cycle of eribulin treatment. EMT markers (E-cadherin, claudin-3, vimentin, and N-cadherin) were analyzed using western blotting. EMT changes were evaluated based on the ratio of epithelial to mesenchymal markers before and after treatment in individual tumors. E-cadherin/vimentin, claudin-3/vimentin, E-cadherin/N-cadherin, and claudin-3/N-cadherin ratios were significantly higher after treatment (p = .007, p = .005, p = .006, and p = .011, respectively). Based on E-cadherin/vimentin, 65.0% of tumors shifted to an epithelial phenotype, as compared to 66.7% based on claudin-3/vimentin, 84.6% based on E-cadherin/N-cadherin, and 71.4% based on claudin-3/N-cadherin ratios. Thus, our results showed that eribulin suppressed EMT in breast cancer tissues.

The usefulness of preoperative exocrine function evaluated by the 13C-trioctanoin breath test as a significant physiological predictor of pancreatic fistula after pancreaticoduodenectomy.

BACKGROUND: The association between pancreatic fistula (PF) after pancreaticoduodenectomy (PD) and preoperative exocrine function is yet to be elucidated. This study aimed to evaluate the association between the preoperative results of the 13C-trioctanoin breath test and the occurrence of PF, showing the clinical relevance of the breath test in predicting PF. METHOD: A total of 80 patients who underwent 13C-trioctanoin breath tests prior to PD from 2006 to 2018 were included in this study. Univariate and multivariate analyses were conducted to reveal the preoperative predictors of PF, showing the association between 13C-trioctanoin absorption and PF incidence. RESULTS: Among 80 patients (age, 68.0 ± 11.9 years, 46 males and 34 females; 30 pancreatic ductal adenocarcinoma [PDAC]/50 non-PDAC patients), the incidence of PF was 12.5% (10/80). Logistic regression analysis results revealed that the frequency of PF increased significantly as the 13C-trioctanoin breath test value (Aa% dose/h) increased (odd's ratio: 1.082, 95% confidence interval: 1.007-1.162, p = 0.032). Moreover, the optimal cutoff value of the preoperative fat absorption level to predict PF was 38.0 (sensitivity, 90%; specificity, 74%; area under the curve, 0.78; p = 0.005). Indeed, the incidence of PF was extremely higher in patients whose breath test value was greater than 38.0 (33%, 9/27) compared with that in patients with values less than 38.0 (1.8%, 1/53). CONCLUSIONS: Favorable preoperative fat absorption evaluated using the 13C-trioctanoin breath test is a feasible and objective predictor of PF after PD.

A preserved pancreatic exocrine function after pancreatectomy may be a crucial cause of pancreatic fistula: paradoxical results of the 13C-trioctanoin breath test in the perioperative period.

PURPOSE: The aim of this study was to elucidate the association between pancreatic fistula (PF) and the sequential changes in the perioperative exocrine function after pancreatectomy. METHODS: The subjects were 96 patients who underwent a 13C-trioctanoin breath test before and 1 month after pancreatectomy, between 2006 and 2018. We retrospectively compared the pre- and postoperative fat absorption levels between patients with PF (PF group; n = 17) and without PF (non-PF group; n = 79) using the breath test. RESULTS: The preoperative level of 13C-trioctanoin absorption (%dose/h) was comparable between the non-PF and PF groups (36.5 vs. 36.9). In the non-PF group, 13C-trioctanoin absorption was significantly decreased after surgery in comparison to the preoperative setting (post-operative 28.5; pre-operative 36.5; p < 0.0001), whereas these values were comparable (post-operative 36.9; pre-operative 34.5; p = 0.129) in the PF group. Moreover, postoperative absorption in the PF group was significantly better than that in the non-PF group (34.5 vs. 28.5%, p = 0.0003). The maximum drain amylase level was significantly higher in patients with a 13C-trioctanoin absorption level (%dose/h) of ≥ 30 in comparison to patients with levels of < 30 (2502 vs. 398 U/L, p = 0.001). CONCLUSION: PF did not exacerbate the pancreatic exocrine function in the early postoperative period, and the acceleration or preservation of the exocrine function after surgery may be an important cause of PF.

Differences in clinicopathologic features and subtype distribution of invasive breast cancer between elderly and non-elderly women.

OBJECTIVES: This study aimed to investigate the clinicopathologic features and subtype distribution of invasive breast cancer in elderly women (≥70 years of age). METHODS: This retrospective study of 1,130 women compared the clinicopathologic characteristics and subtype distribution of invasive breast cancer in elderly (≥70 years) versus non-elderly (<70 years) women. Tumors were classified into five distinct subtypes based on the immunohistochemistry status of estrogen receptor (ER), progesterone receptor (PR), Ki67, and human epidermal growth factor receptor 2 (HER2). RESULTS: The two patient groups did not differ significantly regarding ER and HER2 status. Breast cancers in elderly women were more likely to have negative PR status (40.4% vs. 32.6%, P=0.033) and low Ki67 expression (62.0% vs. 54.4%, P=0.047) than those in non-elderly women. Elderly women were less likely to undergo axillary lymph node dissection and axillary surgery (P<0.001). Consequently, unknown node status was more common in elderly women than non-elderly women (11.1% vs. 1.4%, respectively, P<0.001), while node involvement was less common in elderly women than non-elderly women (26.9% vs. 37.7%, respectively, P<0.001). There was no significant difference in the distribution of subtypes between the two groups. CONCLUSIONS: Breast cancers in elderly women were less frequently node positive and more frequently PR negative and with low Ki67 expression than those in non-elderly women. Moreover, there was no difference in subtype distribution between the two age groups.

Negative progesterone receptor status correlates with increased risk of breast cancer recurrence in luminal B HER2-positive and -negative subtypes.

OBJECTIVES: The prognostic significance of the progesterone receptor (PR) has been widely investigated in luminal A and luminal B [human epidermal growth factor receptor 2 (HER2)-] breast cancer subtypes, both of which are estrogen receptor (ER)-positive and HER2-negative. In contrast, few studies have focused on PR status in luminal B (HER2+) tumors. The aim of this study was to evaluate the impact of positive PR status on outcomes in patients with luminal B (HER2-) or luminal B (HER2+) breast cancer. METHODS: Survival analysis was performed to estimate the likelihood of distant recurrence and death in 469 breast cancer patients with the luminal B (HER2-) or luminal B (HER2+) subtype. The relationship between PR and HER2 status was also assessed. RESULTS: Of 387 luminal B (HER2-) and 82 luminal B (HER2+) cancers, PR+ was significantly more frequent in the former than the latter (86.3% vs. 61.0%, respectively; P<0.001). In univariate analysis, PR was identified as a significant favorable prognostic factor for distant disease-free survival and overall survival in both subtypes, but in multivariate analysis PR was not an independent prognostic factor. CONCLUSIONS: After patients with luminal B subtype were divided into two subgroups according to HER2 status, there was evidence of a relatively good prognosis in the PR+ subgroup. Further studies with a larger number of patients are recommended to validate these findings.

Upregulation of CIP2A in estrogen depletion-resistant breast cancer cells treated with low-dose everolimus.

Everolimus (EVE), an inhibitor of mammalian target of rapamycin, is an emerging second-line therapeutic option for hormone therapy-resistant breast cancers. However, some patients do not respond to EVE, whereas in others it exacerbates the disease. Cellular inhibitor of protein phosphatase 2A (CIP2A) is a human oncoprotein that can promote cancer cell growth and apoptosis resistance. Although CIP2A is upregulated in hormone-related cancers, such as breast cancer, little is known about potential anti-tumor effects of downregulating CIP2A. As a model to study the resistance of breast cancer cells to hormone treatment, we previously established clones of long-term estrogen depletion-resistant MCF-7 (LTED) cells. Here, we selected three clones highly responsive to EVE and three clones poorly responsive to EVE. When cells were treated with EVE, CIP2A mRNA expression was decreased in highly responsive EVE clones (DC-cells) whereas it was increased in poorly responsive EVE clones (IC-cells). Using Kaplan-Meier survival plots, we report that high expression of CIP2A was associated with significantly reduced overall survival in patients with luminal A breast cancer. In IC-cells, cell growth was enhanced upon EVE treatment whereas an EVE range of 0.1-100 nm decreased growth in DC-cells. The mRNA expression of genes involved in epithelial-mesenchymal transition (EMT) such as CDH1, CLDN3, and CK19 was significantly decreased in IC-cells, but remained unchanged in DC-cells. These findings highlight a relationship between CIP2A and EMT in the intrinsic resistance of hormone therapy-resistant breast cancers to EVE.

Oncoplastic breast surgery combining partial mastectomy with immediate breast reshaping using multiple local flaps for a patient with slim body.

Oncoplastic breast surgery (OBS), which combines the concepts of oncologic and plastic surgery, is becoming more common worldwide. We report the results of OBS in a Japanese patient with early breast cancer located on the outer lower quadrant area. We performed OBS combining partial mastectomy with immediate breast reshaping using multiple adipofascial cutaneous flaps and free dermal fat graft because she refused any other OBS. We selected three local flaps to repair the defect. Perioperative and postoperative complications were not seen. The cosmetic findings 3 years after surgery were not excellent, but the patient was satisfied with the results. OBS combining partial mastectomy with immediate breast reshaping using a combination of several flaps was successfully performed in a patient with early breast cancer.

Inverse correlation between Ki67 expression as a continuous variable and outcomes in luminal HER2-negative breast cancer.

OBJECTIVES: Few studies to date have investigated the prognostic significance of Ki67 expression as a continuous variable in breast cancer. This study aimed to evaluate the impact of Ki67 expression as a dichotomous or continuous variable on outcomes in estrogen receptor (ER)+ and human epidermal growth factor receptor 2 (HER2)- breast cancer. METHODS: Survival analysis was performed to estimate the likelihood of distant recurrence and death in retrospective data from 794 patients with ER+/HER2- breast cancer. We assessed the relationship between outcomes and two Ki67 cutoffs, 14% and 20%, and the Ki67 labeling index as a continuous variable. RESULTS: In univariate analysis, T stage, lymph node involvement, histological grade, progesterone receptor status, and Ki67 expression at the two cutoffs and as a continuous variable were identified as significant prognostic factors for distant disease-free survival (DDFS) and overall survival (OS). There were no statistical differences in DDFS and OS between women with Ki67 expression of <14% and 14-<20%. Multivariate analysis showed that Ki67 expression ≥20% was an independent prognostic indicator for DDFS. Regarding the risk of distant metastasis, the 20% cutoff was more reliable than 14%. We also found that Ki67 expression as a continuous variable was an independent prognostic factor for DDFS and OS in multivariate analyses. CONCLUSIONS: High Ki67 expression is associated with a survival disadvantage in patients with ER+/HER2- breast cancer, indicating that these patients might have a higher risk of recurrence after primary treatment and might therefore benefit from individualized treatment.

Differences in clinicopathologic features and subtype distribution of invasive breast cancer between women older and younger than 40 years.

OBJECTIVES: We investigated and compared clinicopathologic features and subtype distribution of invasive breast cancer among women <40 and ≥40 years of age. METHODS: We retrospectively compared clinicopathologic characteristics and subtype distribution of invasive breast cancer in women <40 and ≥40 years of age, in a cohort of 1,130 patients. Subtypes included luminal A (positive for hormone receptors [HR]-estrogen receptor [ER] and/or progesterone receptor [PR]-and negative for human epidermal growth factor receptor 2 [HER2] with low Ki67), luminal B (HER2-) (HR+/HER2-/Ki67High), luminal B (HER2+) (HR+/HER2+), HER2-overexpressing (HR-/HER2+), and triple negative (ER-/PR-/HER2-). RESULTS: Breast cancers in younger women had unfavorable clinicopathologic characteristics, including larger tumors and more frequent node involvement. Subtypes among the 1,130 tumors were luminal A: 36.4%, luminal B (HER2-): 35.0%, luminal B (HER2+): 7.5%, HER2-overexpressing: 7.1%, and triple negative: 14.0%. The age groups significantly differed in subtype distribution (P<0.001). Luminal A subtype was more common in the older group (38.5%) than the younger group (16.2%), and luminal B (HER2-) was more common in the younger group (52.2%) than in the older group (33.2%; P<0.001). CONCLUSIONS: Breast cancers in women younger than 40 years have unfavorable clinicopathologic characteristics and are more likely to be luminal B (HER2-) and less likely to be luminal A than breast cancers in older women.

HMGA1a Induces Alternative Splicing of the Estrogen Receptor-αlpha Gene by Trapping U1 snRNP to an Upstream Pseudo-5' Splice Site.

Objectives: The high-mobility group A protein 1a (HMGA1a) protein is known as a transcription factor that binds to DNA, but recent studies have shown it exerts novel functions through RNA-binding. We were prompted to decipher the mechanism of HMGA1a-induced alternative splicing of the estrogen receptor alpha (ERα) that we recently reported would alter tamoxifen sensitivity in MCF-7 TAMR1 cells. Methods: Endogenous expression of full length ERα66 and its isoform ERα46 were evaluated in MCF-7 breast cancer cells by transient expression of HMGA1a and an RNA decoy (2'-O-methylated RNA of the HMGA1a RNA-binding site) that binds to HMGA1a. RNA-binding of HMGA1a was checked by RNA-EMSA. In vitro splicing assay was performed to check the direct involvement of HMGA1a in splicing regulation. RNA-EMSA assay in the presence of purified U1 snRNP was performed with psoralen UV crosslinking to check complex formation of HMGA1a-U1 snRNP at the upstream pseudo-5' splice site of exon 1. Results: HMGA1a induced exon skipping of a shortened exon 1 of ERα in in vitro splicing assays that was blocked by the HMGA1a RNA decoy and sequence-specific RNA-binding was confirmed by RNA-EMSA. RNA-EMSA combined with psoralen UV crosslinking showed that HMGA1a trapped purified U1 snRNP at the upstream pseudo-5' splice site. Conclusions: Regulation of ERα alternative splicing by an HMGA1a-trapped U1 snRNP complex at the upstream 5' splice site of exon 1 offers novel insight on 5' splice site regulation by U1 snRNP as well as a promising target in breast cancer therapy where alternative splicing of ERα is involved.

Forskolin increases the effect of everolimus on aromatase inhibitor-resistant breast cancer cells.

Aromatase inhibitor (AI) resistance is a major obstacle in the treatment of estrogen receptor-positive breast cancer. Everolimus (EVE) ameliorates AI-resistant breast cancer and is therefore used in cancer treatment. However, some patients show resistance to EVE. Here, we used 30 clones of long-term estrogen-deprived (LTED) MCF-7 cells as a model of AI-resistant breast cancer. We examined changes in protein phosphatase type 2A (PP2A) and cancerous inhibitor of PP2A (CIP2A), a negative regulator of PP2A, in LTED cells treated with EVE. In LTED cells with high sensitivity to EVE, CIP2A expression decreased at low EVE concentrations; however, in LTED cells poorly sensitive to EVE, CIP2A and PP2A did not change upon exposure to EVE. Therefore, we hypothesized that there is a relation between expression of CIP2A and sensitivity to EVE. Knockdown of CIP2A increased the sensitivity to EVE in three clones poorly sensitive to EVE. Additionally, we found that treatment with FSK, which activates PP2A, increased the sensitivity of the cells to EVE. Our data point to CIP2A and PP2A as novel therapeutic targets for AI-resistant breast cancer.

HMGA1a induces alternative splicing of estrogen receptor alpha in MCF-7 human breast cancer cells.

The high-mobility group A protein 1a (HMGA1a) protein is known as an oncogene whose expression level in cancer tissue correlates with the malignant potential, and known as a component of senescence-related structures connecting it to tumor suppressor networks in fibroblasts. HMGA1 protein binds to DNA, but recent studies have shown it exerts novel functions through RNA-binding. Our previous studies have shown that sequence-specific RNA-binding of HMGA1a induces exon-skipping of Presenilin-2 exon 5 in sporadic Alzheimer disease. Here we show that HMGA1a induced exon-skipping of the estrogen receptor alpha (ERα) gene and increased ERα46 mRNA expression in MCF-7 breast cancer cells. An RNA-decoy of HMGA1a efficiently blocked this event and reduced ERα46 protein expression. Blockage of HMGA1a RNA-binding property consequently induced cell growth through reduced ERα46 expression in MCF-7 cells and increased sensitivity to tamoxifen in the tamoxifen-resistant cell line, MCF-7/TAMR1. Stable expression of an HMGA1a RNA-decoy in MCF-7 cells exhibited decreased ERα46 protein expression and increased estrogen-dependent tumor growth when these cells were implanted in nude mice. These results show HMGA1a is involved in alternative splicing of the ERα gene and related to estrogen-related growth as well as tamoxifen sensitivity in MCF-7 breast cancer cells.

A Hypoglycemia-inducing Giant Borderline Phyllodes Tumor Secreting High-molecular-weight Insulin-Like Growth Factor II: Immunohistochemistry and a Western Blot Analysis.

A 50-year-old woman with a large right breast mass was emergently hospitalized for generalized weakness and fatigue. A histological examination of tumor biopsy specimens revealed a phyllodes tumor (PT). She suddenly lost consciousness due to severe hypoglycemia. Non-islet cell tumor hypoglycemia (NICTH) due to the PT was suspected. The tumor was emergently resected. A histological examination revealed a borderline PT. The patient recovered from the hypoglycemic episode. High-molecular-weight insulin-like growth factor II was detected in serum that had been collected preoperatively and in the tumor tissue, but not in serum that had been collected postoperatively. We herein present a case of a borderline PT with NICTH.

Characterization of the Capsule Surrounding Smooth and Textured Tissue Expanders and Correlation with Contracture.

Capsular contracture is a common complication after breast augmentation surgery. This study pathologically evaluated the soft-tissue response to surface modifications in both smooth and textured tissue expander prostheses. METHODS: Smooth tissue expanders and textured tissue expanders in 5 cases each were used for breast reconstruction after mastectomy. Histological samples were harvested from the capsules when the tissue expanders were replaced by silicone implants. Collagen orientation and cellular responses were assessed histologically. Capsular contracture was evaluated using the Baker classification 6 months and 2 years after the removal of the tissue expander. RESULTS: The capsules surrounding the smooth tissue expanders tended to produce more contracture than those surrounding the textured tissue expanders. The collagen architecture of the capsules of the smooth tissue expanders showed random orientation with fragmentation. Conversely, the capsules of the textured tissue expanders showed parallel orientation with collagen bundles of almost normal structure. Significantly more fibrils of elastin and myofibroblasts were found in the capsules surrounding the smooth tissue than in those surrounding the textured ones. CONCLUSIONS: The collagen fibers surrounding the smooth tissue expanders could be cracked during expansion, which may lead to scarring and contracture. Conversely, the collagen orientation surrounding the textured tissue expanders was excellent. Moreover, the increase in elastic fibers and myofibroblasts in the capsules surrounding the smooth tissue expanders may be associated with in vivo contraction patterns. Therefore, the surface type of tissue expanders affects capsular contraction after replacement with definitive implants.

Estradiol suppresses phosphorylation of ERα serine 167 through upregulation of PP2A in breast cancer cells.

Aromatase inhibitors (AIs) are effective endocrine therapeutics for postmenopausal women with estrogen receptor (ER)α-positive breast cancer. However, the efficacy of the treatment is often limited by the onset of AI resistance, owing to the phosphorylation of ERα serine 167 (Ser167). Previous studies have indicated that hyperactivation of the phosphoinositide-3 kinase/RAC serine/threonine-protein kinase signaling pathway occurs in AI-resistant breast cancer models, which coincides with elevated levels of ERα phosphorylation at Ser167. The tumor suppressor serine/threonine-protein phosphatase 2A (PP2A) regulates the phosphatidylinositol 3-kinase/RAC serine/threonine-protein kinase signaling pathway. A previous study indicated that PP2A inhibition decreased ERα Ser167 phosphorylation and estradiol (E2)-independent cell growth. The present study investigated the potential relevance of PP2A in E2 deprivation-resistant MCF-7 cells. E2 depletion reduced the susceptibility of MCF-7 cells to inhibitors of mechanistic target of rapamycin (mTOR) and significantly increased ERα Ser167 phosphorylation and decreased expression of PP2A. Conversely, long-term E2-deprived (LTED) MCF-7 cells, a model of AI-resistant breast cancer, exhibited decreased ERα Ser167 phosphorylation and further upregulation of PP2A in E2-containing medium. The PP2A activator forskolin (FSK) significantly inhibited LTED cell proliferation by increasing the effect of everolimus (Eve), an mTOR inhibitor. In summary, the present study provides further evidence that PP2A represents a therapeutic target for AI-resistant breast cancer.

Sex steroid hormones in pairs of tumor and serum from breast cancer patients and pathobiological role of androstene-3ß, 17ß-diol.

Estrogens play an important role in the pathobiology of breast cancer. In postmenopausal women, peripheral synthesis of estrogens from adrenal/ovarian androgens, dehydroepiandrosterone (DHEA) or androstenedione (Adione), by estrogen-metabolizing enzymes is important. Besides estrone (E1) and estradiol (E2), androgen metabolites, such as androstene-3ß, 17ß-diol (Aenediol) or 5α-androstane-3ß, 17ß-diol (Aanediol), are known to have estrogenic functions, although they have been studied much less in breast cancer. To precisely elucidate steroid metabolism in breast cancer patients and to identify the pathobiological role of estrogenic androgen metabolites, concentrations of DHEA, Adione, Aenediol, Aanediol, E1, and E2 in pairs of serum and tumor tissue from patients with primary breast cancer were measured by liquid chromatography-tandem mass spectrometry. Cell proliferation assays using Aenediol were performed for four breast cancer cell lines. Serous E2 concentration was extremely low in postmenopausal women; however, a marked increase in tumor tissue was observed in hormone receptor-positive cases. E1 concentration, in contrast, was sustained at a higher level, even in postmenopausal serum, and did not increase in tumor tissue irrespective of the hormone receptor status. Dehydroepiandrosterone was most abundant in all samples, and exhibited a similar pattern as Adione and Aenediol. 5α-Androstane-3ß, 17ß-diol was undetectable in most samples. Androstene-3ß, 17ß-diol proliferated estrogen receptor-apositive breast cancer cells in the absence of E2. The intratumoral increase of E2, but not E1, in hormone receptor-positive postmenopausal breast cancer tissue, as well as the proliferative role of Aenediol, was elucidated.

Alternative use of multiple exons 1 of aromatase gene in cancerous and normal breast tissues from women over the age of 80 years.

INTRODUCTION: Peripherally localized aromatase, which converts circulating androgens into estrogens, is important in the pathogenesis of postmenopausal breast carcinomas. We have previously shown that aromatase mRNA levels are higher in elderly breast carcinomas (EldCa) than breast carcinomas of the control group (ContCa) or normal breast tissues. Aromatase expression has been reported to be regulated through the alternative use of multiple exons 1 (exons 1a-1f and so on); however, the preferential usage of exons 1 in elderly breast tissue has never been systematically examined. In order to properly treat and protect against EldCa, the regulation mechanism of aromatase expression in elderly breast tissues should be elucidated. The aim of the present study is to elucidate whether there are any specific patterns in use of multiple exons 1 in elderly breast tissue. METHODS: Usage of multiple exons 1 of the aromatase gene and mRNA levels of aromatase were examined by reverse transcription-polymerase chain reaction analysis in breast tissues of 38 elderly patients with breast cancer (age 80-99), and the results were compared with those in 35 patients of the control group (age 37-70). One-factor analysis of variance and the Scheffé test were used for the comparison of aromatase mRNA levels. Patterns of preferential utilization of multiple exons 1 of the aromatase gene were compared by chi2 test for independence or Fisher exact test for independence using a contingency table. RESULTS: Exon 1d was utilized much more frequently in elderly tissue than in the control group irrespective of cancerous or normal tissue (EldCa, 36/38, 95% versus ContCa, 7/35, 20%, P < 0.0001; normal tissue of the elderly, EldNorm, 30/34, 88% versus normal tissue of controls, ContNorm, 2/29, 7%, P < 0.0001). Twenty EldCa (53%) and 12 EldNorm (35%) used both exons 1c and 1d; however, their dominance was reversed (EldCa, all 1d > 1c; EldNorm, all 1c > 1d). CONCLUSIONS: Elderly breast tissues exhibited specific patterns in use of multiple exons 1, which at least partly explained the higher aromatase levels in EldCa. The mechanisms of how these specific patterns occur during aging and carcinogenesis should be further examined.

Expression level of enzymes related to in situ estrogen synthesis and clinicopathological parameters in breast cancer patients.

In order to evaluate the importance of estrogen production in tumor and surrounding tissues, we measured mRNA expression levels of 5 enzymes participating to estrogen synthesis in situ and 4 breast cancer-related proteins in 27 pairs of tumor and non-malignant tissues. Steroid sulfatase (STS) mRNA was more frequently detected in tumor tissues rather than in their non-malignant counterparts. Estrogen sulfotransferase (EST) was constantly expressed with high level not only in tumor tissues but also in their surrounding non-malignant counterparts. In contrast, mRNA expression levels of aromatase, and 17beta-hydroxysteroid dehydrogenase type I and II were relatively low and detected only in small proportion of the patients. We also measured the mRNA expression levels of the same nine genes in tumor tissues of 197 breast cancer patients, and analyzed relationship between the mRNA expression level and the clinicopathological parameters. The mRNA expression levels of STS, aromatase and erbB2 in tumor tissues increased as breast cancer progressed. The tumoral mRNA expression levels of STS, estrogen receptor beta, and erbB2 in patients with recurrence were higher than those in patients without recurrence. Upregulation of STS expression plays an important role in tumor progression of human breast cancer and is considered to be responsible for estrogen production in tumor and surrounding tissues.

Recent perspectives of endocrine therapy for breast cancer.

The choice of endocrine therapy for breast cancer depends on the menopausal status and stage of disease. Endocrine therapy remains the first choice and most important component in the treatment of hormone sensitive non-life threatening advanced breast cancer. In premenopausal women with metastatic disease, the combination of a luteinizing hormone-releasing hormone (LH-RH) agonist plus tamoxifen is reasonable as first-line endocrine therapy. In postmenopausal patients with recurrent disease progressing after or during adjuvant tamoxifen, third-generation aromatase inhibitors (AIs) are the preferred first-line endocrine treatment. Many premenopausal and postmenopausal women with hormone responsive breast cancer benefit from sequential use of endocrine therapies at the time of disease progression. Recent clinical trials designs have been implemented, employing AIs as monotherapy in postmenopausal breast cancer patients, as first-line adjuvant therapy, and in sequence either 2-3 or 5 years, with initial tamoxifen. Emerging results from these trials indicate an advantage to patients for any of these strategies, and most international guidelines now suggest the use of an AI in the adjuvant setting in postmenopausal women. The use of endocrine treatment for metastatic and early breast cancer will be reviewed here.