BACKGROUND:A woman, mother of one at the age of 19 years, was diagnosed with mammary adenocarcinoma in the right breast in 1985 at the age of 37 years. The patient underwent surgery (quadrantectomy), lymphadenectomy and radiotherapy. In 1999, an adenocarcinoma was diagnosed in the left breast, followed by adequate resection, radiotherapy and anti-oestrogen receptor treatment for 6 years. In March 2014, an infiltrating adenocarcinoma was diagnosed in the remaining part of the right breast that had been operated on and irradiated in 1985.

CASE REPORT:The pre-surgical biopsy, showed weak positivity for progesterone receptor (PgR) (<1%), high positivity for oestrogen receptor (ER) (90%), high positivity for human epidermal growth factor receptor (HER2) (>10%, score 2+), and high positivity for the nuclear protein Ki67 (30%). In the three weeks between diagnosis and operation, when no other treatment had been planned, the patient decided to self-administer high doses of oral vitamin D3 (10,000 IU/day), and to follow a strict ketogenic diet.

RESULTS:Following right mastectomy, analysis of the surgical specimen showed no positivity for HER2 expression (negative, score 0), and significant increase in positivity of PgR (20%). Positivity for ER and Ki67 were unaltered.

CONCLUSION:This observation indicates that a combination of high-dose vitamin D3 and ketogenic diet leads to changes in some biological markers of breast cancer, i.e. negativization of HER2 expression and increased expression of PgR.

OBJECTIVES: This study compares the effects of an integrated yoga program with brief supportive therapy in breast cancer outpatients undergoing adjuvant radiotherapy at a cancer centre. METHODS: Eighty-eight stage II and III breast cancer outpatients were randomly assigned to receive yoga (n = 44) or brief supportive therapy (n = 44) prior to their radiotherapy treatment. Intervention consisted of yoga sessions lasting 60 min daily while the control group was imparted supportive therapy once in 10 days. Assessments included European Organization for Research in the Treatment of Cancer-Quality of Life (EORTCQoL C30) functional scales and Positive and Negative Affect Schedule (PANAS). Assessments were done at baseline and after 6 weeks of radiotherapy treatment. RESULTS: An intention to treat GLM repeated measures ANOVA showed significant difference across groups over time for positive affect, negative affect and emotional function and social function. There was significant improvement in positive affect (ES = 0.59, p = 0.007, 95%CI 1.25 to 7.8), emotional function (ES = 0.71, p = 0.001, 95%CI 6.45 to 25.33) and cognitive function (ES = 0.48, p = 0.03, 95%CI 1.2 to 18.5), and decrease in negative affect (ES = 0.84, p<0.001, 95%CI -13.4 to -4.4) in the yoga group as compared to controls. There was a significant positive correlation between positive affect with role function, social function and global quality of life. There was a significant negative correlation between negative affect with physical function, role function, emotional function and social function. CONCLUSION: The results suggest a possible role for yoga to improve quality of life and affect in breast cancer outpatients.

OBJECTIVE:The purpose of this clinical trial was to determine the efficacy of a dynamic computerized infrared imaging system for distinguishing between benign and malignant lesions in patients undergoing biopsy on the basis of mammographic findings.

SUBJECTS AND METHODS:A 4-year clinical trial was conducted at five institutions using infrared imaging of patients for whom breast biopsy had been recommended. The data from a blinded subject set were obtained in 769 subjects with 875 biopsied lesions resulting in 187 malignant and 688 benign findings. The infrared technique records a series of sequential images that provides an assessment of the infrared information in a mammographically identified area. The suspicious area is localized on the infrared image by the radiologist using mammograms, and an index of suspicion is determined, yielding a negative or positive result.

RESULTS:In the 875 biopsied lesions, the index of suspicion resulted in a 97% sensitivity, a 14% specificity, a 95% negative predictive value, and a 24% positive predictive value. Lesions that were assessed as false-negative by infrared analysis were microcalcifications, so an additional analysis was performed in a subset excluding lesions described only as microcalcification. In this restricted subset of 448 subjects with 479 lesions and 110 malignancies, the index of suspicion resulted in a 99% sensitivity, an 18% specificity, a 99% negative predictive value, and a 27% positive predictive value. Analysis of infrared imaging performance in all 875 biopsied lesions revealed that specificity was statistically improved in dense breast tissue compared with fatty breast tissue.

CONCLUSION:Infrared imaging offers a safe noninvasive procedure that would be valuable as an adjunct to mammography in determining whether a lesion is benign or malignant.

OBJECTIVE:To compare the efficacy difference in treatment of depression in breast cancer between the combined therapy of acupuncture and auricular acupressure and western medication.

METHODS:Sixty patients were randomized into an observation group and a control group, 30 cases in each one. In the observation group, the combined therapy of acupuncture and auricular acupressure was adopted. The main acupoints of acupuncture were Hegu (LI 4), Tai-chong (LR 3), Baihui (GV 20), Zusanli (ST 36), Qihai (CV 6), etc. The supplementary acupoints were combined according to the syndrome differentiation. The treatment was given once every day, 5 treatments a week, at the interval of 2 days among weeks. The auricular acupressure was applied to gan (CO12, liver), pi (CO13, spleen), neifenmi (CO18, endocrine), etc., once every 4 days, on each side in one treatment. In the control group, fluoxetine hydrochloride capsules were prescribed for oral administration, 20 mg, once a day. The Hamilton depression rating scale (HAMD) was used to assess the disease severity and efficacy before treatment, in 4 and 8 weeks of treatment separately. HAMD factor changes were observed before treatment and at the end of the 8th week. The Asberg antidepressants scale (SERS) was applied to safety assessment.

RESULTS:The total effective rate was 86.7% (26/30) in the observation group, better than 63.3% (19/30) in the control group (P<0.05). At the end of the 4th and 8th weeks, HAMD scores were all reduced apparently in the two groups (all P<0.01). At the end of the 8th week, the scores of the HAMD factor 1 (anxiety/somatic system), factor 5 (retardation) and factor 6 (sleep disturbance) were all reduced as compared with those before treatment in the two groups (all P<0.01); the results in the observation group were better than those in the control group (P<0.05, P<0.01). SERS score in the observation group was lower obviously than that in the control group (P<0.01).

CONCLUSION:The combined therapy of acupuncture and auricular acupressure achieves the antidepression effect in treatment of depression in breast cancer and has less side effects and high safety. The efficacy is superior to fluoxetine hydrochloride capsules.

OBJECTIVE:To compare the efficacy difference in treatment of depression in breast cancer between the combined therapy of acupuncture and auricular acupressure and western medication.

METHODS:Sixty patients were randomized into an observation group and a control group, 30 cases in each one. In the observation group, the combined therapy of acupuncture and auricular acupressure was adopted. The main acupoints of acupuncture were Hegu (LI 4), Tai-chong (LR 3), Baihui (GV 20), Zusanli (ST 36), Qihai (CV 6), etc. The supplementary acupoints were combined according to the syndrome differentiation. The treatment was given once every day, 5 treatments a week, at the interval of 2 days among weeks. The auricular acupressure was applied to gan (CO12, liver), pi (CO13, spleen), neifenmi (CO18, endocrine), etc., once every 4 days, on each side in one treatment. In the control group, fluoxetine hydrochloride capsules were prescribed for oral administration, 20 mg, once a day. The Hamilton depression rating scale (HAMD) was used to assess the disease severity and efficacy before treatment, in 4 and 8 weeks of treatment separately. HAMD factor changes were observed before treatment and at the end of the 8th week. The Asberg antidepressants scale (SERS) was applied to safety assessment.

RESULTS:The total effective rate was 86.7% (26/30) in the observation group, better than 63.3% (19/30) in the control group (P<0.05). At the end of the 4th and 8th weeks, HAMD scores were all reduced apparently in the two groups (all P<0.01). At the end of the 8th week, the scores of the HAMD factor 1 (anxiety/somatic system), factor 5 (retardation) and factor 6 (sleep disturbance) were all reduced as compared with those before treatment in the two groups (all P<0.01); the results in the observation group were better than those in the control group (P<0.05, P<0.01). SERS score in the observation group was lower obviously than that in the control group (P<0.01).

CONCLUSION:The combined therapy of acupuncture and auricular acupressure achieves the antidepression effect in treatment of depression in breast cancer and has less side effects and high safety. The efficacy is superior to fluoxetine hydrochloride capsules.

BACKGROUND:Although fatigue, sleep disturbance, depression, and anxiety are associated with pain in breast cancer patients, it is unknown whether acupuncture can decrease these comorbid symptoms in cancer patients with pain. The objective of this study was to evaluate the effect of electroacupuncture (EA) on fatigue, sleep, and psychological distress in breast cancer survivors who experience joint pain related to aromatase inhibitors (AIs).

METHODS:The authors performed a randomized controlled trial of an 8-week course of EA compared with a waitlist control (WLC) group and a sham acupuncture (SA) group in postmenopausal women with breast cancer who self-reported joint pain attributable to AIs. Fatigue, sleep disturbance, anxiety, and depression were measured using the Brief Fatigue Inventory (BFI), the Pittsburgh Sleep Quality Index (PSQI), and the Hospital Anxiety and Depression Scale (HADS). The effects of EA and SA versus WLC on these outcomes were evaluated using mixed-effects models.

RESULTS:Of the 67 randomly assigned patients, baseline pain interference was associated with fatigue (Pearson correlation coefficient [r]=0.75; P<.001), sleep disturbance (r=0.38; P=.0026), and depression (r=0.58; P<.001). Compared with the WLC condition, EA produced significant improvements in fatigue (P=.0095), anxiety (P=.044), and depression (P=.015) and a nonsignificant improvement in sleep disturbance (P=.058) during the 12-week intervention and follow-up period. In contrast, SA did not produce significant reductions in fatigue or anxiety symptoms but did produce a significant improvement in depression compared with the WLC condition (P=.0088).

CONCLUSIONS:Compared with usual care, EA produced significant improvements in fatigue, anxiety, and depression; whereas SA improved only depression in women experiencing AI-related arthralgia.

Indisputably, cancer is a global crisis that requires immediate intervention. Despite the use of conventional treatments over the past decades, it is acceptable to admit that these are expensive, invasive, associated with many side effects and, therefore, a reduced quality of life. One of the most possible solutions to this could be the use of gold nanoparticle (AuNP) conjugated photodynamic therapy (PDT) in combination with cannabidiol (CBD), aderivative from the. Since the use ofhas always been associated with recreation and psychoactive qualities, the positive effects ofor its derivatives on cancer treatment have been misunderstood and hence misinterpreted. On the other hand, AuNP-PDT is the most favoured form of treatment for cancer, due to its augmented specificity and minimal risk of side effects compared to conventional treatments. However, its use requires the consideration of several physical, biologic, pharmacologic and immunological factors, which may hinder its effectiveness if not taken into consideration. In this review, the role of gold nanoparticle mediated PDT combined with CBD treatment on breast cancer cells will be deliberated.

PURPOSE:The Exercise for Health trials were randomised, controlled trials designed to evaluate an 8-month pragmatic exercise intervention, commencing 6 weeks post-surgery for women with newly diagnosed breast cancer residing in urban or rural/regional Australia. For these exploratory analyses, the primary and secondary outcomes were overall survival (OS) and disease-free survival (DFS), respectively.

METHODS:Consenting urban- (n = 194) and rural/regional-residing women (n = 143) were randomised to exercise (intervention delivered face-to-face or by telephone) or usual care. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI) for survival outcomes (exercise group,n = 207, 65% urban women; usual care group, n = 130, 46% urban women).

RESULTS:After a median follow-up of 8.3 years, there were 11 (5.3%) deaths in the exercise group compared with 15 (11.5%) deaths in the usual care group (OS HR for the exercise group: 0.45, 95% CI 0.20-0.96; p = 0.04). DFS events for the exercise versus usual care group were 25 (12.1%) and 23 (17.7%), respectively (HR: 0.66, 95% CI 0.38-1.17; p = 0.16). HRs for OS favoured exercise irrespective of age, body mass index, stage of disease, intervention compliance, and physical activity levels at 12 months post-diagnosis, although were stronger (p < 0.05) for younger women, women with stage II + disease, women with 1 + comorbidity at time of diagnosis, higher intervention compliance and for those who met national physical activity guidelines at 12 months post-diagnosis.

CONCLUSION:An exercise intervention delivered during and beyond treatment for breast cancer, and that was designed to cater for all women irrespective of place of residence and access to health services, has clear potential to benefit survival. Trial numbers: ACT RN: 012606000233527; ACT RN: 12609000809235.

Exercise is associated with favorable changes in circulating immune cells and improved survival in early-stage breast cancer patients, but the mechansims remain to be fully elucidated. Preclinical studies indicate that physical activity started before tumor injection reduces tumor incidence and progression. Here we tested whether exercise has anti-tumor effects in mice with established 4T1 mammary carcinoma, a mouse model of triple negative breast cancer. Exercise slowed tumor progression and reduced the tumor-induced accumulation of myeloid-derived suppressor cells (MDSCs). The reduction in MDSCs was accompanied by a relative increase in natural killer and CD8 T cell activation, suggesting that exercise restores a favorable immune environment. Consistently, exercise improved responses to a combination of programmed cell death protein 1 (PD-1) blockade and focal radiotherapy. These data support further investigations of exercise in breast cancer patients treated with combinations of immunotherapy and cytotoxic agents to improve cancer outcomes.

Regular physical activity protects against the development of breast and colon cancer, since it reduces the risk of developing these by 25-30%. During exercise, humoral factors are released from the working muscles for endocrinal signaling to other organs. We hypothesized that these myokines mediate some of the inhibitory effects of exercise on mammary cancer cell proliferation. Serum and muscles were collected from mice after an exercise bout. Incubation with exercise-conditioned serum inhibited MCF-7 cell proliferation by 52% and increased caspase activity by 54%. A similar increase in caspase activity was found after incubation of MCF-7 cells with conditioned media from electrically stimulated myotubes. PCR array analysis (CAPM-0838E; SABiosciences) revealed that seven genes were upregulated in the muscles after exercise, and of these oncostatin M (OSM) proved to inhibit MCF-7 proliferation by 42%, increase caspase activity by 46%, and induce apoptosis. Blocking OSM signaling with anti-OSM antibodies reduced the induction of caspase activity by 51%. To verify that OSM was a myokine, we showed that it was significantly upregulated in serum and in three muscles, tibialis cranialis, gastronemius, and soleus, after an exercise bout. In contrast, OSM expression remained unchanged in subcutaneous and visceral adipose tissue, liver, and spleen (mononuclear cells). We conclude that postexercise serum inhibits mammary cancer cell proliferation and induces apoptosis of these cells. We suggest that one or more myokines secreted from working muscles may be mediating this effect and that OSM is a possible candidate. These findings emphasize that role of physical activity in cancer treatment, showing a direct link between exercise-induced humoral factors and decreased tumor cell growth.

Slow drug release at the tumor tissue and poor tumor penetration are two big challenges for the successful application of nanosystems in tumor therapy. Here, we report that a high concentration of the natural reducing agent vitamin C (VC) triggers rapid extracellular PTX release from PTX-loaded shell-sheddable PEG-SS-PCL micelles (SSM) in tumors in vivo. An in vivo tolerance study showed that VC at a blood concentration of 40mM had little toxicity to nude mice. Notably, SSM rapidly disassembled and released the payloads (Cy5 or PTX) in response to 40mM VC. In vivo near-infrared imaging of tumor-bearing mice showed that with post-injection of VC to establish a blood concentration of 40mM, Cy5 was quickly released from the micelles and diffused deep into the tumor tissue. Biodistribution studies revealed that 6h after the injection of PTX-loaded micelles the highest tumor accumulation was reached, which was set as the injection time for VC. The antitumor efficacy of a combination therapy of PTX-loaded micelles and VC was evaluated in both MCF-7 and U87MG tumor models. In both tumor models, single injections of VC didn't show any antitumor effect, while sequential administration of PTX-loaded SSM and VC exhibited significantly higher tumor inhibition effects and better survival rates as compared to single treatment with PTX-loaded micelles, demonstrating that exogenous administration of VC effectively triggered the release of PTX from SSM in vivo. The combination of reduction-sensitive nanomedicines with exogenous VC appears a promising approach to achieve potent treatment of malignant tumors.

Photodynamic therapy (PDT), as a clinical cancer therapy, is a mild therapy, which involves application of photosensitizers (PSs) which located in target cells and then be irradiated by corresponding wawelength. The activation of PSs generates radical oxygenspecies ( ROS) to exert a selective cytotoxic activity for the target cells. Aloeemodin (AE) has been found to be a anti-tumor agent in many studies, and it also demonstrated to be a photosensitizer in recent years. In order to study the mechanism of aloe-emodin as a photosensitizer. In the present study, we investigated the mechanisms of photo-cytotoxicity induced by aloe-emodin in breast cancer MCF-7 cells. Analysis of cell proliferation evidenced that there was a dramatically depression after photodynamic treatment with aseries of aloe-emodin concentration and light doses showed. We observed changes apoptosis and demonstrated that the mechanisms of apoptosis were involved of mitochondrial and endoplasmic reticulum death pathway. The capacity of adhesion, migration and invasion of breast cells were measured usingWST8 and transwell assay and demonstrated that AE-PDT significantly inhibited adhesion, migration and invasion of MCF-7cells. The expression of MMP2, MMP9, VEGF and Nrf2 demonstrated that the metastasis was related to oxidative stress. Analysis of changes in cytoskeleton components (F-actin) evidenced cytoskeleton disorganization after treatment with AE-PDT. Taken together, the present results indicated that PDT with aloe emodin effectively suppressed cancer development in MCF-7cells, suggesting the potential of AE as one new photosensitizer in PDT can provide a new modility for treating cancer.

Photodynamic therapy (PDT), as a clinical cancer therapy, is a mild therapy, which involves application of photosensitizers (PSs) which located in target cells and then be irradiated by corresponding wawelength. The activation of PSs generates radical oxygenspecies ( ROS) to exert a selective cytotoxic activity for the target cells. Aloeemodin (AE) has been found to be a anti-tumor agent in many studies, and it also demonstrated to be a photosensitizer in recent years. In order to study the mechanism of aloe-emodin as a photosensitizer. In the present study, we investigated the mechanisms of photo-cytotoxicity induced by aloe-emodin in breast cancer MCF-7 cells. Analysis of cell proliferation evidenced that there was a dramatically depression after photodynamic treatment with aseries of aloe-emodin concentration and light doses showed. We observed changes apoptosis and demonstrated that the mechanisms of apoptosis were involved of mitochondrial and endoplasmic reticulum death pathway. The capacity of adhesion, migration and invasion of breast cells were measured usingWST8 and transwell assay and demonstrated that AE-PDT significantly inhibited adhesion, migration and invasion of MCF-7cells. The expression of MMP2, MMP9, VEGF and Nrf2 demonstrated that the metastasis was related to oxidative stress. Analysis of changes in cytoskeleton components (F-actin) evidenced cytoskeleton disorganization after treatment with AE-PDT. Taken together, the present results indicated that PDT with aloe emodin effectively suppressed cancer development in MCF-7cells, suggesting the potential of AE as one new photosensitizer in PDT can provide a new modility for treating cancer.

Hypoxia-inducible factor-1 (HIF-1) is a heterodimer transcription factor whose elevated activity in many cancers helps them to survive under hypoxic conditions and enhances their capacity to grow invasively, establish metastases, and survive chemo- or radiotherapy. Optimal intracellular levels of ascorbate suppress the level and transcriptional activity of HIF-1under normoxic or mildly hypoxic conditions by supporting the activity of proly and asparagyl hydroxylases that target HIF-1alpha. High intracellular ascorbate can also work in various ways to down-regulate activation of NF-kappaB which, like HIF-1 is constitutively active in many cancers and promotes aggressive behavior - in part by promoting transcription of HIF-1alpha. Yet recent evidence suggests that, even in the context of adequate ascorbate nutrition, the intracellular ascorbate content of many aggressive cancers may be supoptimal for effective HIF-1 control. This likely reflects low expression or activity of the SVCT2 ascorbate transporter. The expression of SVCT2 in cancers has so far received little study; but the extracellular acidity characteristic of many tumors would be expected to reduce the activity of this transporter, which has a mildly alkaline pH optimum. Unfortunately, since SVCT2 has a high affinity for ascorbate, and its activity is nearly saturated at normal healthy serum levels of this vitamin, increased oral administration of ascorbate would be unlikely to have much impact on the intracellular ascorbate content of tumors. However, cancers in which HIF-1 is active express high levels of glucose transporters such as GLUT-1, and these transporters can promote influx of dehydroascorbic acid (DHA) via facilitated diffusion; once inside the cell, DHA is rapidly reduced to ascorbate, which effectively is"trapped"within the cell. Hence, episodic intravenous infusions of modest doses of DHA may have potential for optimizing the intracellular ascorbate content of cancers, potentially rendering them less aggressive. Indeed, several published studies have concluded that parenteral DHA--sometimes in quite modest doses--can retard the growth of transplanted tumors in rodents. As an alternative or adjunctive strategy, oral administration of sodium bicarbonate, by normalizing the extracellular pH of tumors, has the potential to boost the activity of SCTV2 in tumor cells, thereby promoting increased ascorbate uptake. Indeed, the utility of oral sodium bicarbonate for suppressing metastasis formation in nude mice xenografted with a human breast cancer has been reported. Hence, oral sodium bicarbonate and intravenous DHA may have the potential to blunt the aggressiveness of certain cancers in which suboptimal intracellular ascorbate levels contribute to elevated HIF-1 activity.

Breast cancer (BC) is the second leading cause of cancer death among women worldwide. The main cause of BC morbidity and mortality is the invasiveness capacity of cancer cells that may lead to metastasis. Here, we aimed to investigate the therapeutic efficacy ofextract (GLE)-a medicinal mushroom with anticancer properties-on BC motility via the Rac/Lamellipodin pathway. GLE treatment effects were tested on MDA-MB-231 breast cancer cells. The effects were tested on cell viability, migration and invasion. Pulldowns, immunoblotting, and immunofluorescence were used to measure Rac activity and the expression of proteins involved in cell migration and in lamellipodia formation, respectively. As a result, GLE suppressed BC cell viability, migration, and invasion capacity. GLE impaired Rac activity, as well as downregulated Lamellipodin, ENA/VASP, p-FAK (Tyr925), Cdc42, and c-Myc expression. Lamellipodia formation was significantly reduced by GLE. In conclusion, we demonstrate that GLE reduces Rac activity and downregulates signaling molecules involved in lamellipodia formation. These novel findings serve as basis for further studies to elucidate the potential of GLE as a therapeutic agent regulating the Rac/Lamellipodin pathway in BC metastasis.

ETHNOPHARMACOLOGICAL RELEVANCE:Cordyceps sinensis is a traditional Chinese medicine and has been used as adjuvant treatments for cancer and it has been also demonstrated to be effective in cancer patients.

AIM OF THE STUDY:The objective of the present study is to investigate the anti-metastasis effects of water extracts of Cordyceps sinensis (WECS) in breast cancer and the potential mechanisms.

MATERIALS AND METHODS:The cytotoxicity of WECS on 4T1 breast cancer cells was evaluated in vitro using cell counting kit-8 (CCK8) assay. The in vivo anti-metastatic activity of intraperitoneally administered WECS and its effect on animal survival were measured in a mouse breast cancer metastasis model. To explore the molecular mechanisms of the anti-metastasis effect of WECS, the expression of matrix metalloprotein-9 (MMP-9) in serum was determined by enzyme-linked immunosorbent assay (ELISA). In addition, a protein array was used to examine the cytokine expression profiles in lung homogenates.

RESULTS:Treatment with WECS (0.10-0.40mg/ml) significantly inhibited 4T1 cell viability in vitro. In animal studies, 50mg/kg WECS significantly reduced the number of metastatic lung nodules and the weight of lung, without affecting body weight of mice. Furthermore, WECS increased the survival rate of 4T1 tumor bearing mice in a dose dependent manner, and at high dose, WECS (50mg/kg) significantly increased the life span of the mice compared to untreated control group. The expression level of MMP-9 in serum was decreased about 50% in 50mg/kg WECS treated group compared to control group. The results of protein array showed that the expression of CC chemokine ligand 17 (CCL17), MMP-9, osteopontin (OPN), interleukin-33 (IL-33), CC chemokine ligand 12 (CCL12) and CC chemokine ligand 6 (CCL6) in the lungs of 4T1 tumor bearing mice was increased more than two fold compared with normal mice. Among them, the expression of CCL17, MMP-9, OPN, IL-33 was significantly reduced by treatment of 50mg/kg WECS.

CONCLUSION:Our results demonstrated that WECS has potent anti-metastasis activity in a mouse breast cancer metastasis model possibly by down-regulation the expression of several metastasis-related cytokines.

The medical mushroom Ganoderma lucidum (Reishi), a traditional Chinese medicine, has exhibited a promising anti-cancer effect. However, the molecular mechanism of its action on cancer cells remains unclear. Aberrant activation of Wnt/β-catenin signaling pathway is the cause of many types of cancer, including breast cancer. Here we investigated the effect of Reishi on Wnt/β-catenin signaling pathway and elucidated the molecular mechanism of its function in inhibiting breast cancer cells. We found that Reishi blocked Wnt/β-catenin signaling through inhibiting the phosphorylation of Wnt co-receptor LRP6. In human (MDA-MB-231) and mouse (4T1) breast cancer cell lines, Reishi significantly decreased the phosphorylation of LRP6 and suppressed Wnt3a-activated Wnt target gene Axin2 expression. Administration of Reishi inhibitedWnt-induced hyper-proliferation of breast cancer cells and MDA-MB-231 cell migration. Our results provide evidence that Reishi suppresses breast cancer cell growth and migration through inhibiting Wnt/β-catenin signaling pathway, indicating that Reishi may be a potential natural inhibitor for breast cancer.

The high incidence of resistance to Tyrosine Kinase Inhibitors (TKIs) targeted against EGFR and downstream pathways has increased the necessity to identify agents that may be combined with these therapies to provide a sustained response for breast cancer patients. Here, we investigate the therapeutic potential of Ganoderma lucidum extract (GLE) in breast cancer, focusing on the regulation of the EGFR signaling cascade when treated with the EGFR TKI, Erlotinib. SUM-149, or intrinsic Erlotinib resistant MDA-MB-231 cells, and a successfully developed Erlotinib resistant cell line, rSUM-149 were treated with increasing concentrations of Erlotinib, GLE, or their combination (Erlotinib/GLE) for 72h. Treatment effects were tested on cell viability, cell proliferation, cell migration and invasion. To determine tumor progression, severe combined immunodeficient mice were injected with SUM-149 cells and then treated with Erlotinib/GLE or Erlotinib for 13 weeks. We assessed the protein expression of ERK1/2 and AKT in in vitro and in vivo models. Our results show that GLE synergizes with Erlotinib to sensitize SUM-149 cells to drug treatment, and overcomes intrinsic and developed Erlotinib resistance. Also, Erlotinib/GLE decreases SUM-149 cell viability, proliferation, migration and invasion. GLE increases Erlotinib sensitivity by inactivating AKT and ERK signaling pathways in our models. We conclude that a combinatorial therapeutic approach may be the best way to increase prognosis in breast cancer patients with EGFR overexpressing tumors.

Ganoderma lucidum, an oriental medical mushroom, has been used in Asia for the prevention and treatment of a variety of diseases, including cancer. We have previously demonstrated that G. lucidum inhibits growth and induces cell cycle arrest at G0/G1 phase through the inhibition of Akt/NF-kappaB signaling in estrogen-independent human breast cancer cells. However, the molecular mechanism(s) responsible for the inhibitory effects of G. lucidum on the proliferation of estrogen-dependent (MCF-7) and estrogen-independent (MDA-MB-231) breast cancer cells remain to be elucidated. Here, we show that G. lucidum inhibited the proliferation of breast cancer MCF-7 and MDA-MB-231 cells by the modulation of the estrogen receptor (ER) and NF-kappaB signaling. Thus, G. lucidum down-regulated the expression of ERalpha in MCF-7 cells but did not effect the expression of ERbeta in MCF-7 and MDA-MB-231 cells. In addition, G. lucidum inhibited estrogen-dependent as well as constitutive transactivation activity of ER through estrogen response element (ERE) in a reporter gene assay. G. lucidum decreased TNF-alpha-induced (MCF-7) as well as constitutive (MDA-MB-231) activity of NF-kappaB. The inhibition of ER and NF-kappaB pathways resulted in the down-regulation of expression of c-myc, finally suppressing proliferation of estrogen-dependent as well as estrogen-independent cancer cells. Collectively, these results suggest that G. lucidum inhibits proliferation of human breast cancer cells and contain biologically active compounds with specificity against estrogen receptor and NF-kappaB signaling, and implicate G. lucidum as a suitable herb for chemoprevention and chemotherapy of breast cancer.

Ganoderma lucidum (Reishi, Lingzhi) is a popular Asian mushroom that has been used for more than 2 millennia for the general promotion of health and was therefore called the "Mushroom of Immortality." Ganoderma lucidum was also used in traditional Chinese medicine to prevent or treat a variety of diseases, including cancer. We previously demonstrated that Ganoderma lucidum suppresses the invasive behavior of breast cancer cells by inhibiting the transcription factor NF-kappaB. However, the molecular mechanisms responsible for the inhibitory effects of Ganoderma lucidum on the growth of highly invasive and metastatic breast cancer cells has not been fully elucidated. Here, we show that Ganoderma lucidum inhibits proliferation of breast cancer MDA-MB-231 cells by downregulating Akt/NF-kappaB signaling. Ganoderma lucidum suppresses phosphorylation of Akt on Ser473 and downregulates the expression of Akt, which results in the inhibition of NF-kappaB activity in MDA-MB-231 cells. The biological effect of Ganoderma lucidum was demonstrated by cell cycle arrest at G0/G1, which was the result of the downregulation of expression of NF-kappaB-regulated cyclin D1, followed by the inhibition of cdk4. Our results suggest that Ganoderma lucidum inhibits the growth of MDA-MB-231 breast cancer cells by modulating Akt/NF-kappaB signaling and could have potential therapeutic use for the treatment of breast cancer.