Abstract: d-limonene is a bioactive food component found in high concentration in citrus peel oil with anticancer effects in preclinical studies of mammary carcinogenesis. Extrapolation of preclinical data to human cancer is limited, in part, by inadequate information on the oral bioavailability and tissue disposition of d-limonene in humans. As a fat-soluble compound, d-limonene is more likely to deposit in fatty tissues such as the breast. To assess disposition of d-limonene in humans, we conducted a pilot study of oral d-limonene-rich lemonade. Following a 1-wk washout period devoid of citrus, healthy adults consumed 40 oz. of freshly prepared lemonade containing 500 to 600 mg d-limonene daily for 4 wk. On the first and last consumption days, blood and buttock fat biopsy were collected. Matched preintervention and postintervention fat biopsies (n = 7), and matched preintervention and postintervention plasma samples (n = 6), were analyzed for d-limonene levels using gas chromatography and mass spectrometry. There was a significant increase in d-limonene levels in the fat biopsies after 4 wk (P = 0.009); initial levels ranged from nondetectable to 7.79 micromol/kg tissue, and postintervention levels ranged from 53.6 to 294 micromol/kg tissue. Plasma d-limonene levels increased from 0.35 to 0.72 micromol/l initially to postintervention levels of 0.54 to 1.65 micromol/l (P = 0.016). Postintervention adipose d-limonene levels were 51.0 to 195 times higher than plasma levels (P = 0.009). Our results demonstrate accumulation of d-limonene in adipose tissue after oral dosing and support additional studies of d-limonene for chemoprevention in tissues such as the breast that are comprised of a significant fat fraction.
Abstract: The BRCA-1 protein is a tumor suppressor involved in repair of DNA damage. Epigenetic mechanisms contribute to its reduced expression in sporadic breast tumors. Through diet, humans are exposed to a complex mixture of xenobiotics and natural ligands of the aromatic hydrocarbon receptor (AhR), which contributes to the etiology of various types of cancers. The AhR binds xenobiotics, endogenous ligands, and many natural dietary bioactive compounds, including the phytoalexin resveratrol (Res). In estrogen receptor- alpha (ER alpha )-positive and BRCA-1 wild-type MCF-7 breast cancer cells, we investigated the influence of AhR activation with the agonist 2,3,7,8 tetrachlorobenzo(p)dioxin (TCDD) on epigenetic regulation of the BRCA-1 gene and the preventative effects of Res. We report that activation and recruitment of the AhR to the BRCA-1 promoter hampers 17 beta -estradiol (E2)-dependent stimulation of BRCA-1 transcription and protein levels. These inhibitory effects are paralleled by reduced occupancy of ER alpha , acetylated histone (AcH)-4, and AcH3K9. Conversely, the treatment with TCDD increases the association of mono-methylated-H3K9, DNA-methyltransferase-1 (DNMT1), and methyl-binding domain protein-2 with the BRCA-1 promoter and stimulates the accumulation of DNA strand breaks. The AhR-dependent repression of BRCA-1 expression is reversed by small interference for the AhR and DNMT1 or pretreatment with Res, which reduces TCDD-induced DNA strand breaks. These results support the hypothesis that epigenetic silencing of the BRCA-1 gene by the AhR is preventable with Res and provide the molecular basis for the development of dietary strategies based on natural AhR antagonists.
Abstract: OBJECTIVE:: Dietary intake of vitamin D and calcium may be related to risk of breast cancer, possibly by affecting mammographic density. However, the few studies that have evaluated the association between these nutrients and mammographic density in postmenopausal women have had inconsistent results. METHODS:: We conducted a cross-sectional analysis in 808 participants of the Mammogram Density Ancillary Study of the Women's Health Initiative. Mammographic percent density was measured using baseline mammograms taken before randomization of participants in the intervention trials. Vitamin D and calcium intake was assessed with a validated food frequency questionnaire and an inventory of current supplement use, both completed at baseline. RESULTS:: After adjustment for age, body mass index, regional solar irradiance, and other factors, we did not find a relationship between vitamin D or calcium intake and mammographic density. Mean mammographic percent densities in women reporting total vitamin D intakes of less than 100, 100 to 199, 200 to 399, 400 to 599, and 600 or greater IU/day were 5.8%, 10.4%, 6.2%, 3.8%, and 5.1%, respectively (P trend = 0.67). Results in women reporting a total calcium intake of less than 500, 500 to 749, 750 to 999, 1,000 to 1,199, and 1,200 or greater mg/day were 7.3%, 4.9%, 7.3%, 6.9%, and 7.11%, respectively (P trend = 0.51). We did not observe any effect modification by overall level of mammographic density or solar irradiance, but supplemental vitamin D use was associated with lower density in younger women (P interaction = 0.009). CONCLUSIONS:: These findings do not support a relationship between dietary vitamin D or calcium intake and mammographic density in postmenopausal women. Additional studies should explore these associations in women of different ages and in relation to serum vitamin D levels.
Abstract: The purposes of this investigation were to compare psychological distress among cancer survivors' social network members with different relationships with the survivors and to compare their reported levels of distress with population norms. Participants in this investigation included spouses/significant others (n = 153), siblings (n = 11), adult children (n = 25), parents (n = 10), cousins (n = 6), and friends/others (n = 10) of English or Spanish speaking women with breast cancer and English speaking men with prostate cancer. Network members reported on their symptoms of depression, positive and negative affect, anxiety, and relationship satisfaction. The psychological distress among all relationship types was similar. Spouses, and to a lesser extent, adult children were the only groups whose levels of psychological distress were above population norms. Relationship satisfaction was negatively associated with social network members' psychological distress, and female network members had higher levels of depression than male network members due, in part, to higher perceived stress among female network members. These findings highlight the need to consider the potentially deleterious impact of cancer not just on survivors' spouses, but on other social network members as well and to make services available to network members who may play an important role in the survivor's care and adjustment.
Abstract: The direct detection of native proteins in heterogeneous solutions remains a challenging problem. Standard methodologies rely on a separation step to circumvent nonspecific signal generation. We hypothesized that a simple and general method for the detection of native proteins in solution could be achieved through ternary complexation, where the conditional signal generation afforded by split-protein reporters could be married to the specificity afforded by either native receptors or specific antibodies. Toward this goal, we describe a solution phase split-luciferase assay for native protein detection, where we fused fragmented halves of firefly luciferase to separate receptor fragments or single-chain antibodies, allowing for conditional luciferase complementation in the presence of several biologically significant protein targets. To demonstrate the utility of this strategy, we have developed and validated assay platforms for the vascular endothelial growth factor, the gp120 coat protein from HIV-1, and the human epidermal growth factor receptor 2 (HER2), a marker for breast cancer. The specificities of the recognition elements, CD4 and the 17b single-chain antibody, employed in the gp120 sensor allowed us to parse gp120s from different clades. Our rationally designed HER2 sensing platform was capable of discriminating between HER2 expression levels in several tumor cell lines. In addition, luminescence from reassembled luciferase was linear across a panel of cell lines with increasing HER2 expression. We envision that the proof of principle studies presented herein may allow for the potential detection of a broad range of biological analytes utilizing ternary split-protein systems.
Abstract: Lymphedema or tissue swelling from impaired lymph drainage commonly occurs after regional nodal dissection and/or radiation therapy for cancer control. Treatment options for this disabling and life-altering complication involve long-term labor-intensive commitments. Sentinel node biopsy can forestall removal of negative regional nodes, offering some protection against lymphedema, however, most preventive measures are elusive, ineffective, or unproven. Our goal was to determine whether the radioprotectant amifostine could prevent or retard the development of lymphedema in a rodent radiation therapy-dependent model yet not offer tumor protection from the therapeutic effects of radiation therapy. We pre-treated rats after unilateral radical groin dissection with the organic thiophosphate radioprotectant amifostine or placebo prior to single dose post-operative groin radiation therapy and monitored hindlimb volumes, wound scores, and tissue lymphostasis. In addition, we determined whether amifostine protected human MCF7 breast cancer cells exposed to a range of radiation therapy doses in an in vitro clonogenic assay and an in vivo MCF7 tumor xenograft model. Our findings indicate that amifostine markedly reduced the volume of limb lymphedema and dramatically improved wound healing and tissue lymphostasis in the rodent lymphedema model. The in vivo and in vitro studies further demonstrated that amifostine offered no MCF7 tumor protection from radiation therapy. These pre-clinical findings provide proof-of-principle to further delineate specific mechanisms underlying amifostine's beneficial effects, determine optimal amifostine-radiation therapy dosing regimens, and thereby expedite translation into clinical trials to reduce lymphedema incidence and severity in cancer patients at high lymphedema risk in whom radiation therapy is the recommended therapy.
Abstract: Background. Primary ovarian carcinoma with metastasis to the breast is rare, with only 39 cases reported in the current literature. Ovarian metastasis to the breast presenting as inflammatory breast carcinoma is even more infrequent, with only 6 cases reported.Case. We present a patient who developed metastatic inflammatory cancer of the breast from a stage IIIC papillary serous ovarian adenocarcinoma approximately 1 year after the original diagnosis. Pathologic analysis confirmed the origin of the tumor: a high-grade adenocarcinoma morphologically similar to the previously diagnosed ovarian cancer. In addition, the tumor was strongly positive on immunohistochemistry for CA-125, identical to the ovarian primary. The patient died of diffuse metastasis 5 months after the breast tumor was noted.Conclusion. Although ovarian metastasis to the breast presenting as inflammatory breast cancer is rare, it should be included in the differential diagnosis for any patient with a personal history of ovarian cancer. Accurate differentiation is necessary because treatment differs significantly for patients with ovarian metastasis to the breast, as compared with patients with primary inflammatory breast cancer. Ovarian metastasis to the breast confers a poor prognosis: patient survival ranged from 3 to 18 months, with a median survival of 6 months after the diagnosis of the breast metastasis.
Abstract: Abstract Background: Overweight status after breast cancer treatment may increase a woman's risk for recurrent disease and/or early onset cardiovascular disease. Green tea has been proposed to promote weight loss and favourably modify glucose, insulin and blood lipids. This pilot study tested the effect of daily decaffeinated green tea consumption for 6 months on weight and body composition, select metabolic parameters and lipid profiles in overweight breast cancer survivors. Methods: The effect of daily decaffeinated green tea intake on weight, body composition and changes in resting metabolic rate, energy intake, glucose, insulin, homeostasis model assessment - insulin resistance (HOMA-IR) and lipids was evaluated in overweight breast cancer survivors. Participants had a mean weight of 80.2 kg; body mass index (BMI) 30.1 kg m(-2); and body fat 46.4%. Participants (n = 54) were randomised to 960 mL of decaffeinated green or placebo tea daily for 6 months. Results: Mean (SD) tea intake among study completers (n = 39) was 5952 (1176) mL week(-1) and was associated with a significant reduction in energy intake (P = 0.02). Change in body weight of -1.2 kg (green tea) versus +0.2 kg (placebo) suggests a weight change effect, although this was not statistically significant. Decaffeinated green tea intake was associated with elevated high-density lipoprotein (HDL) levels (P = 0.003) and nonsignificant improvements in the HDL/LDL ratio and HOMA-IR (-1.1 +/- 5.9: green tea; +3.2 +/- 7.2: herbal). Conclusions: Intake of decaffeinated green tea for 6 months was associated with a slight reduction in body weight and improved HDL and glucose homeostasis in overweight breast cancer survivors.
Abstract: In this commentary, we discuss the challenges of considering breast cancer as a set of discrete diseases in epidemiologic studies. Using this malignancy as an example, we argue for the use of the case-only study design as an important initial step in understanding the extent of etiologic heterogeneity by assessing the relative association between correlation of the established risk factors and the different tumor subtypes.
