The prevalence of intrinsic subtypes and prognosis in breast cancer patients of different races

A recent report indicated that a high prevalence of basal-like breast tumors (estrogen receptor [ER]-negative, progesterone receptor [PR]-negative, human epidermal growth factor receptor [HER] 2-negative, and cytokeratin 5/6-positive and/or HER1-positive) could contribute to a poor prognosis in African American women with breast cancer. It has been reported that Japanese women with breast cancer have a significantly better survival rate than other races in the USA. These findings suggest that breast cancers in Japanese women have favorable biological characteristics. To clarify this hypothesis, we conducted a cohort study to investigate the prevalence of intrinsic subtypes and prognosis for each subtype in 793 Japanese patients. This study revealed a very low prevalence (only 8%) of basal-like breast tumors with aggressive biological characteristics in Japanese patients. Survival analysis showed a significantly poorer prognosis in patients with basal-like tumors than in those with luminal A tumors (ER- and/or PR-positive, and HER2-negative) with favorable biological characteristics. These findings support the hypothesis that breast cancers in Japanese women have more favorable biological characteristics and a better prognosis than those in other races. In conclusion, the prevalence of basal-like breast tumors could influence the prognosis of breast cancer patients of different races. The prevalence of intrinsic subtypes should be taken into account when analyzing survival data in a multi-racial/international clinical study.     

Genotype–Phenotype Correlations of Malignant Hyperthermia and Central Core Disease Mutations in the Central Region of the RYR1 Channel

Type 1 ryanodine receptor (RYR1) is a Ca²⁺ release channel in the sarcoplasmic reticulum of skeletal muscle and is mutated in some muscle diseases, including malignant hyperthermia (MH) and central core disease (CCD). Over 200 mutations associated with these diseases have been identified, and most mutations accelerate Ca²⁺‐induced Ca²⁺ release (CICR), resulting in abnormal Ca²⁺ homeostasis in skeletal muscle. However, it remains largely unknown how specific mutations cause different phenotypes. In this study, we investigated the CICR activity of 14 mutations at 10 different positions in the central region of RYR1 (10 MH and four MH/CCD mutations) using a heterologous expression system in HEK293 cells. In live‐cell Ca²⁺ imaging, the mutant channels exhibited an enhanced sensitivity to caffeine, a reduced endoplasmic reticulum Ca²⁺ content, and an increased resting cytoplasmic Ca²⁺ level. The three parameters for CICR (Ca²⁺ sensitivity for activation, Ca²⁺ sensitivity for inactivation, and attainable maximum activity, i.e., gain) were obtained by [³H]ryanodine binding and fitting analysis. The mutant channels showed increased gain and Ca²⁺ sensitivity for activation in a site‐specific manner. Genotype–phenotype correlations were explained well by the near‐atomic structure of RYR1. Our data suggest that divergent CICR activity may cause various disease phenotypes by specific mutations.     

A selective,high affinity 5‐HT2B receptor antagonist inhibits visceral hypersensitivity in rats

Background RS‐127445 is a selective, high affinity 5‐HT_2Breceptor antagonist. We investigated whether 5‐HT_2Breceptor antagonists can reduce colonic visceral hypersensitivity caused by restraint stress or by proximal colonic inflammation. Methods Visceral hypersensitivity was induced in rats by either restraint stress or injection of 2, 4, 6‐trinitrobenzene sulfonic acid (TNBS) into the proximal colon. Restraint stress produced a significant increase in numbers of abdominal contractions evoked by colorectal distension (CRD), measured as a quantitative index of visceral nociception in rats. Seven days after TNBS injection, the pain threshold to CRD at the non‐inflamed distal colon, that was determined as the minimum pressure required to evoke abdominal cramp, was significantly decreased. The effect of RS‐127445 on visceral hypersensitivity was assessed in either naïve or TNBS‐treated rats. Key Results Oral administration of a selective, high affinity 5‐HT_2Breceptor antagonist, RS‐127445, significantly inhibited visceral hypersensitivity provoked by restraint stress (35 to 74% inhibition at 1 to 10 mg kg^?1). Oral RS‐127445 produced a significant suppression of TNBS‐induced visceral hypersensitivity (15 to 62% inhibition at 3 to 30 mg kg^?1), although it was without significant effect on the visceral nociceptive threshold of naïve rats. RS‐127445 (1 to 30 mg kg^?1, p.o.) also dose‐dependently reduced the restraint stress‐induced defecation in naïve and TNBS‐treated rats. Conclusions & Inferences These results suggest that 5‐HT_2Breceptors are involved in signaling from the colon in rats in which there is visceral hypersensitivity and that a selective 5‐HT_2Breceptor antagonist could have therapeutic potential for the treatment of gut disorders characterized by visceral hypersensitivity.     

A new human breast cancer cell line, KPL-3C, secretes parathyroid hormone-related protein and produces tumours associated with microcalcifications in nude mice.

Parathyroid hormone-related protein (PTHrP) is the main cause of humoral hypercalcaemia of malignancy (HHM). We recently established a new human breast cancer cell line, designated KPL-3C, from the malignant effusion of a breast cancer patient with HHM. Morphological, cytogenetic and immunohistochemical analyses indicated that the cell line is derived from human breast cancer. The KPL-3C cells stably secrete immunoreactive PTHrP measured by a two-site immunoradiometric assay, possess both oestrogen and progesterone receptors and are tumorigenic in female nude mice. The addition of phorbol-12-myristate-13-acetate to the medium significantly increased PTHrP secretion from the cells. In contrast, hydrocortisone, medroxyprogesterone acetate and 22-oxacalcitriol decreased PTHrP secretion in a dose-dependent manner. Unexpectedly, a number of microcalcifications were observed in the transplanted tumours. Radiographical examination indicated that the microcalcifications in the tumours are very similar to those commonly observed in human breast cancer. These findings suggest that this KPL-3C cell line may be useful for studying the regulatory mechanisms of PTHrP secretion and the mechanisms that lead to the deposition of microcalcifications in breast cancer.     

Tumor markers in breast cancer

A number of breast cancer-orientated tumor markers have been utilized for various purposes in clinical practice in Japan. Their purposes are as follows: early detection of primary tumors, prediction of disease extent and prognosis, early detection of recurrent diseases, evaluation of therapeutic responses, monitoring patient outcome, and differential diagnosis of metastatic tumors of unknown origin. The clinical significance of the measurement of tumor markers for these purposes is overviewed in this article. In addition, the results are summarized for two clinical studies conducted by the Tumor Marker Study Group of Japanese Breast Cancer Society (Chairperson: Dr. Kurebayashi), a questionnaire survey on the current status of tumor markers in breast cancer in Japan and a multi-institutional study on the utility of tumor markers for evaluation of therapeutic responses. Future directions of clinical and experimental research for breast cancer-orientated tumor markers are also discussed.     

Intratumoral Estrogen Concentration and Expression of Estrogen-Induced Genes in Male Breast Carcinoma: Comparison with Female Breast Carcinoma

It is speculated that estrogens play important roles in the male breast carcinoma (MBC) as well as the female breast carcinoma (FBC). However, estrogen concentrations or molecular features of estrogen actions have not been reported in MBC, and biological significance of estrogens remains largely unclear in MBC. Therefore, we examined intratumoral estrogen concentrations, estrogen receptor (ER) α/ERβ status, and expression profiles of estrogen-induced genes in MBC tissues, and compared these with FBC. 17β-Estradiol concentration in MBC (n?=?4) was significantly (14-fold) higher than that in non-neoplastic male breast (n?=?3) and tended to be higher than that in FBC (n?=?7). Results of microarray analysis clearly demonstrated that expression profiles of the two gene lists, which were previously reported as estrogen-induced genes in MCF-7 breast carcinoma cell line, were markedly different between MBC and FBC. In the immunohistochemistry, MBC tissues were frequently positive for aromatase (63 %) and 17β-hydroxysteroid dehydrogenase type 1 (67 %), but not for steroid sulfatase (6.7 %). A great majority (77 %) of MBC showed positive for both ERα and ERβ, and its frequency was significantly higher than FBC cases. These results suggest that estradiol is locally produced in MBC tissue by aromatase. Different expression profiles of the estrogen-induced genes may associate with different estrogen functions in MBC from FBC, which may be partly due to their ERα/ERβ status.     

Therapeutic efficacy of capecitabine on advanced and recurrent breast cancer with special reference to time to progression

We investigated 29 patients with advanced and recurrent breast cancers who underwent capecitabine therapy in the department. Patients'backgrounds: 41-89 years of age (median, 57 years of age). Advanced breast cancers, 5; recurrent breast cancers, 24. PS< or =2 in 18 cases and PS 3< or =in 11 cases. Eighty-six percent of patients were positive for ER and/or PgR. Multiorgan metastases occurred in 22 cases; bone metastases, 22 cases; lymph node metastases, 12 cases; skin metastases, 11 cases; lung metastases, 10 cases. The rate of patients who received chemotherapy was 93%, and the rate of those who received endocrinotherapy was 90%. Therapeutic response rate was CR in 1 case, PR in 5 cases, long SD in 5 cases, SD in 10 cases and PD in 8 cases, indicating a response rate of 20.7% and a clinical benefit rate of 37.9%. Time to progression (TTP) was 1-15 months (the median time, 4 months). Overall survival time (OS) was 2-23 months (median length, 12 months). OS was significantly longer in patients who had therapeutic effects than in patients with no such effects. TTP was significantly longer in patients who had therapeutic effects and in those who had longer SD than in patients with no such effects. OS was significantly longer in patients who had TTP of 6 months or longer. Clinical benefit (presence vs. absence) and PS (< or =2 vs. 3< or =) were independent factors affecting TTP. Capecitabine is expected to prolong the length of survival in patients who are able to continue treatment for 6 months or longer.