The chemokine receptor CCR7 promotes mammary tumorigenesis through amplification of stem-like cells.

The chemokine receptor CCR7 is widely implicated in breast cancer pathobiology. Although recent reports correlated high CCR7 levels with more advanced tumor grade and poor prognosis, limited in vivo data are available regarding its specific function in mammary gland neoplasia and the underlying mechanisms involved. To address these questions we generated a bigenic mouse model of breast cancer combined with CCR7 deletion, which revealed that CCR7 ablation results in a considerable delay in tumor onset as well as significantly reduced tumor burden. Importantly, CCR7 was found to exert its function by regulating mammary cancer stem-like cells in both murine and human tumors. In vivo experiments showed that loss of CCR7 activity either through deletion or pharmacological antagonism significantly decreased functional pools of stem-like cells in mouse primary mammary tumors, providing a mechanistic explanation for the tumor-promoting role of this chemokine receptor. These data characterize the oncogenic properties of CCR7 in mammary epithelial neoplasia and point to a new route for therapeutic intervention to target evasive cancer stem cells.

Mammographic density-a review on the current understanding of its association with breast cancer.

There has been considerable recent interest in the genetic, biological and epidemiological basis of mammographic density (MD), and the search for causative links between MD and breast cancer (BC) risk. This report will critically review the current literature on MD and summarize the current evidence for its association with BC. Keywords 'mammographic dens*', 'dense mammary tissue' or 'percent dens*' were used to search the existing literature in English on PubMed and Medline. All reports were critically analyzed. The data were assigned to one of the following aspects of MD: general association with BC, its relationship with the breast hormonal milieu, the cellular basis of MD, the generic variations of MD, and its significance in the clinical setting. MD adjusted for age, and BMI is associated with increased risk of BC diagnosis, advanced tumour stage at diagnosis and increased risk of both local recurrence and second primary cancers. The MD measures that predict BC risk have high heritability, and to date several genetic markers associated with BC risk have been found to also be associated with these MD risk predictors. Change in MD could be a predictor of the extent of chemoprevention with tamoxifen. Although the biological and genetic pathways that determine and perhaps modulate MD remain largely unresolved, significant inroads are being made into the understanding of MD, which may lead to benefits in clinical screening, assessment and treatment strategies. This review provides a timely update on the current understanding of MD's association with BC risk.

Differential effects of exogenous androgen and an androgen receptor antagonist in the peri- and postpubertal murine mammary gland.

There is emerging evidence that androgens inhibit proliferation of normal and malignant breast epithelial cells, but the actions of androgens in normal mammary gland morphogenesis are not well understood. In this study, we investigated whether development of the murine mammary gland could be altered by stimulating or suppressing androgen receptor (AR) signaling in vivo. Intact virgin female mice aged 5 wk (midpuberty) or 12 wk (postpuberty) were implanted with slow-release pellets containing either placebo, 5α-dihydrotestosterone (1.5 mg) or the AR antagonist flutamide (60 mg). Treatment with 5α-dihydrotestosterone from midpuberty to 12 wk of age-retarded ductal extension by 40% (P = 0.007), but treatment from 12-21 wk had no significant effect on gland morphology. In contrast, inhibition of AR signaling with flutamide from midpuberty had no effect on the mammary gland, but flutamide treatment from 12-21 wk increased ductal branching (P = 0.004) and proliferation (P = 0.03) of breast epithelial cells. The increased proliferation in flutamide-treated mice was not correlated with serum estradiol levels or estrogen receptor-α (ERα) expression. In control mice, the frequency and intensity of AR immunostaining in mammary epithelial cells was significantly increased in the 12- to 21-wk treatment group compared with the 5- to 12-wk group (P < 0.001). In contrast, no change in ERα occurred, resulting in a marked increase in the AR to ERα ratio from 0.56 (±0.12) to 1.47 (±0.10). Our findings indicate that androgen signaling influences development and structure of the adult mammary gland and that homeostasis between estrogen and androgen signaling in mature glands is critical to constrain the proliferative effects of estradiol.

The mechanistic basis for sexual dysfunction in male transforming growth factor beta1 null mutant mice.

The cytokine transforming growth factor beta1 (TGFB1) is implicated in male sexual function. Previous behavioral studies show that Tgfb1 null mutant mice mount and display limited intromission behavior with receptive females but are unable to complete successful copulation. The studies presented here explore the physiologic basis for sexual dysfunction in Tgfb1 null mutant males. Scanning electron microscopy revealed that the surface of the penis in Tgfb1 null mutant males was abnormally coated in superficial keratinized epithelial cells. There was a significant reduction in protrusion of penile spines through the superficial tissue in Tgfb1 null mutant mice; in some mice, the spines were almost completely embedded. Histologic analysis revealed reduced skin thickness in the penis of Tgfb1 null mutant males. Nerve fibers, endothelial cells, smooth muscle actin, macrophages, and neuronal and inducible nitric oxide synthase were present in similar abundance and location in Tgfb1 null mutant mice compared with wild-type controls; however, an increase in collagen I deposition was detected. Behavioral studies revealed that Tgfb1 null mutant males undergo spontaneous noncontact erections, albeit at a reduced rate compared with control mice, and engage in less frequent genital grooming activity. These studies suggest that Tgfb1 null mutation may adversely influence copulatory behavior through effects on both altered structural integrity of the penile skin and impaired tissue compliance leading to erectile dysfunction.

Differential regulation by FSH and IGF-I of extracellular matrix IGFBP-5 in bovine granulosa cells: effect of association with the oocyte.

Inhibition of insulin-like growth factor (IGF)-I induced DNA synthesis in bovine oocyte-cumulus complexes (OCCs) caused by follicle-stimulating hormone (FSH) has been linked to changes in the extracellular matrix which do not occur in mural granulosa cells (MGCs). We investigated regulation by IGF-I and FSH of secreted and extracellular matrix entrapped IGF-binding proteins. OCCs and MGCs from bovine ovaries were cultured in media supplemented with IGF-I and FSH for 24 h. Culture media and extracellular matrix were analysed for IGF-binding proteins by Western ligand blot and immunoblot and found to contain principally IGFBP-3 and -5. The combined treatment of IGF-I and FSH increased the concentration of IGFBP-3 in OCC and MGC conditioned media by 4- and 6-fold, respectively. Treatment of OCCs and not MGCs with IGF-I and FSH together increased extracellular matrix IGFBP-5 by 2.5-fold. The differential regulation of extracellular matrix IGFBP-5 in OCCs compared to MGCs suggest involvement of changes in the extracellular matrix brought about by IGF-I and FSH in overall regulation of IGF-I in the ovarian follicle.