Cancer Cells In Breast Research Articles

The Activity of Trisindoline 5 Compound againsts c-Myc and FoxO1, 3, 4 Gene Expression on MDA-MB-231 Breast Cancer Stem Cells

Unoptimum curing and controlling proliferation of cancer cells in breast is due to the presence of BCSCs (Breast cancer stem cells), which are associated with stemness, self-renewal, tumour initiation and metastasis. Similarly, overexpression of c-Myc (oncogenic transcription factor) in breast cancer has become potential as target of cancer therapy. Inhibition of c-Myc in cancer cells can increase the transcription factors FoxO family members including FoxO1, 3, 4 and their target genes involved in apoptosis, cell cycle arrest and autophagy. Trisindoline is an indole timer alkaloid natural compound, which is toxic to cancer cells. For this reason, we aim to decide the activity of one of derivate compound of trisindoline, namely as trisindoline 5 on BCSCs MDA-MB-231 through cytotoxicity, apoptosis, and gene expression of c-Myc and FoxO1, 3, 4. As a result, MTT assay showed trisindoline 5 can decrease the viability of BCSCs MDA-MB-231 with IC50 13.127µg/ml. Furthermore, flow cytometry analysis shown that trisindoline 5 can induce apoptosis 5.23% at concentration of 25µg/ml. Similarly, qPCR analysis showed the highest decrease in c-Myc was found in trisindoline 5 concentration of 25µg/ml with 0.0746-fold. Meanwhile, the highest increase FoxO1, 3, 4 expression was found in trisindoline 5 concentration of 25µg/ml, 20.6452-fold, 26.4709-fold, and 12.8341-fold respectively. Therefore, we conclude that trisindoline 5 concentration of 25µg/ml was able to decrease the expression of c-Myc and increase the expression of FoxO1, 3, 4 despites, it was not effective enough in reducing the population of BCSCs MDA-MB-231.

Anticancer Activity of Green Synthesized Manganese Doped Cerium Oxide Nanoparticles Prepared by Using Acacia Concinna Fruit Extract

AbstractPure CeO2 and Ce1‐xMnxO2, where x = 0, 2, 4 and 6% w/w, were synthesized by sol‐gel method using Acacia Concinna fruit extract as a surfactant and stabilizing agent. The synthesized particles were subjected to various characterization techniques, including XRD, HRTEM, FESEM, FTIR, Raman and UV‐Visible spectroscopy. The XRD pattern of the samples demonstrated single phase of CeO2, with cubic fluorite type structure and crystallite size of 6–7 nm. The morphology of the nanoparticles (NPs) was analyzed by FESEM and HRTEM which illustrated an aggregate of irregular spherical nanoparticles and the average particle size is around 18 nm. Raman spectroscopy validated the phase purity and indicated about the structural defects caused by the dopants. The bandgap energy of CeO2 NPs is calculated to be 3.00 eV from the Tauc plot of UV‐Visible spectroscopy, which gradually decreased to 2.43 eV with increase in manganese doping. Cytotoxicity studies signified the role of Mn‐doped CeO2 NPs as a potential nanotherapeutic agent for cancer treatment. The cell viability assay showed that 200 µg/mL of 6% Mn‐doped CeO2 nanoparticles exhibited remarkable cytotoxic effect by inhibiting 50% of cancer cells both in breast and colon cancer cell lines without affecting the healthy cell lines.

Cucurbitacin-E; Curvularia lunata Secondary Metabolite as a BRCA 1 and 2 Regulator in Mice Associated Breast Cancer

Background: Cucurbitacin-induced apoptosis and inhibition of cell growth can render several cancers ineffective. The microbial transformation of cucurbitacin-E-glucoside to cucurbitacin- E was carried out by Curvularia lunata (NRRL 2178). Moreover, in vitro anticancer activity against the MCF-7 cell line as well as in vivo anticancer activity against dimethylbenz (a) anthracene (DMBA)-induced breast cancer in mice using cucurbitacin-E was evaluated. Methods: The cucurbitacin-E-glucoside was biotransformed by Curvularia lunata to cucurbitacin- E, and the isolated compound was tested in vitro against the MCF-7 cell line, and its IC50 was calculated. LD50 of cucurbitacin-E was estimated in mice, and its protective activity against DMBA-induced cancer in mice was studied. Breast cancer induction was done by a single-dose subcutaneous administration of DMBA (50 mg). Plasma ALT, AST, ALP, and LDH, as well as GSH, SOD, GPx, MDA, TNF-α, IL-6, and tumor suppressor P53 assays, were used to assess cucurbitacin- E's capacity to protect the liver and breast against DMBA-induced toxicity. Moreover, by assessing the gene expression of tumor suppressor genes (BRCA 1 and 2) and conducting histopathological analysis, the suppressive effect of cucurbitacin-E was examined. Results: The IC50 value of cucurbitacin-E against MCF-7 cell lines equals 72.15 ± 0.64 μg/ml. LD50 of cucurbitacin-E given orally in adult mice is equal to 1200 mg/kg b.w. The levels of plasma ALT, AST, ALP, and LDH were decreased significantly in DMBA-treated mice when administered with cucurbitacin-E at 1/50 LD50 (24 mg/kg/b.w.) and 1/20 LD50 (60 mg/kg/b.w.). In breast tissue, the levels of GSH, SOD, GPx, and P53 were significantly increased, as were decreased levels of TNF-α, IL-6, P53, and MDA. Conversely, there was a downregulation in the mRNA expression levels of BRCA1 and BRCA2. The histopathological analysis revealed that cucurbitacin-E management improved the tissue architecture of breast tumors. Conclusions: These findings demonstrate the ability of cucurbitacin-E to inhibit cancer cells in the rat breast by controlling oxidative stress and inflammatory biomarkers, as well as downregulating the mRNA expression levels of BRCA1 and BRCA2.

The Immune Response of Cancer Cells in Breast and Gynecologic Neoplasms.

Cancer diseases constitute a major health problem which leads to the death of millions of people annually. They are unique among other diseases because cancer cells can perfectly adapt to the environment that they create themselves. This environment is usually highly hostile and for normal cells it would be hugely difficult to survive, however neoplastic cells not only can survive but also manage to proliferate. One of the reasons is that they can alter immunological pathways which allow them to be flexible and change their phenotype to the one needed in specific conditions. The aim of this paper is to describe some of these immunological pathways that play significant roles in gynecologic neoplasms as well as review recent research in this field. It is of high importance to possess extensive knowledge about these processes, as greater understanding leads to creating more specialized therapies which may prove highly effective in the future.

Novel Bottom-Side Polished PCF-Based Plasmonic Biosensor for Early Detection of Hazardous Cancerous Cells.

This work presents a single-core bowl-shaped bottom-side polished (BSP) photonic crystal fiber (PCF) sensor based on surface plasmon resonance (SPR) concept for the early detection of hazardous cancer cells in human blood, skin, cervical, breast, and adrenal glands. We have studied liquid samples of cancer-affected and healthy samples with their concentrations/refractive indices in the sensing medium. To induce a plasmonic effect in the PCF sensor, the bottom flat section of a silica PCF fiber is coated with a 40nm plasmonic material, such as gold. To strengthen this effect, a thin TiO2 layer of 5 nm is sandwiched between fiber and gold as it strongly holds gold nanoparticles with smooth fiber surface. When the cancer-affected sample is introduced to the sensor's sensing medium, it produces a different absorption peak in the form of a resonance wavelength than the healthy sample. This reallocation of the absorption peak is used to determine sensitivity. Hence, the obtained sensitivities for blood cancer, cervical cancer, adrenal gland cancer, skin cancer, and breast cancer (type-1and type-2) cells are 22,857nm/RIU, 20000nm/RIU, 20714nm/RIU, 20000nm/RIU, 21428nm/RIU, and 25000nm/RIU, respectively, with highest detection limit 0.024. These strong findings indicate that our proposed cancer sensor PCF is a viable choice for early cancer cell detection.

Potential Anticancer Activity of Juniperus procera and Molecular Docking Models of Active Proteins in Cancer Cells.

Medicinal plants provide a wide range of active compounds that can be exploited to create novel medicines with minimal side effects. The current study aimed to identify the anticancer properties of Juniperus procera (J. procera) leaves. Here, we demonstrate that J. procera leaves' methanolic extract suppresses cancer cells in colon (HCT116), liver (HepG2), breast (MCF-7), and erythroid (JK-1) cell lines. By applying GC/MS, we were able to determine the components of the J. procera extract that might contribute to cytotoxicity. Molecular docking modules were created that used active components against cyclin-dependent kinase 5 (Cdk5) in colon cancer, aromatase cytochrome P450 in the breast cancer receptor protein, the -N terminal domain in the erythroid cancer receptor of the erythroid spectrin, and topoisomerase in liver cancer. The results demonstrate that, out of the 12 bioactive compounds generated by GC/MS analysis, the active ingredient 2-imino-6-nitro-2H-1-benzopyran-3-carbothiamide proved to be the best-docked chemical with the chosen proteins impacted by DNA conformational changes, cell membrane integrity, and proliferation in molecular docking studies. Notably, we uncovered the capacity of J. procera to induce apoptosis and inhibit cell growth in the HCT116 cell line. Collectively, our data propose that J. procera leaves' methanolic extract has an anticancer role with the potential to guide future mechanistic studies.

Heat transfer capacity in millimeter size breast cancer cells analysis through thermal imaging and FDNCNN for primary stage identification

In this paper, cancer cells in human breast of below 256 cell (2 cm) counts are detected through proposed Feature DnCNN (FDnCNN) enhancement algorithm. Cancer cell count below 256 is termed as T1b and T1c stages. FDnCNN is applied to the breast thermal images obtained after external heating of breast phantom through warm water. Induced heat due to warm water immersion of breast phantom helps for detection of the small size cancer cell through heat transfer capacity between normal and cancer cells. However, traditional method of breast cancer detection through thermal imaging never detects the cancer cell size of below 2 cm (256-cell) in the images. Thermal imaging breast cancer detects cancer cell of above 256 cells count in breast and never below cancer cell of count 256 cells. The proposed method of acquiring the thermal image after induced heating on the breast phantom, leads to higher interpretation of cancer cells below 256 cell count because of increase in thermogenesis of tissue. The increase in thermogenesis in cancer tissues improves visibility of cancer cell below 256 cell count. Moreover, induced heat based phantom thermal images need enhancement algorithm for better visualization of cancer cell count of below 256. The proposed FDnCNN enhancement algorithm performs better than traditional algorithms and provides an accuracy of cancer cell measurement of about 95%, when compared to ground truth measurement of cancer cells.

The suppressive role of nanoencapsulated chia oil against DMBA-induced breast cancer through oxidative stress repression and tumor genes expression modulation in rats

BackgroundChia oil is high in omega-3 fatty acids, which have been linked to a lower risk of many diseases, including cancer. Oil encapsulation is a method that holds promise for maintaining oil content while enhancing solubility and stability. The purpose of this study is to prepare nanoencapsulated Chia oil and investigate its suppressive effects on rat chemically induced breast cancer.MethodsThe oil was extracted from commercial Chia seeds and their fatty acids were analyzed using Gas Chromatography–mass spectrometry (GC/MS). Sodium alginate was used as a loading agent to create the Chia oil nanocapsules. The DPPH assay was used to assess the oil nanocapsules' capacity to scavenge free radicals. Breast cancer induction was done by single dose subcutaneously administration of 80 mg/kg dimethylbenz (a) anthracene (DMBA). Models of breast cancer were given Chia oil nanocapsules orally for one month at doses of 100 and 200 mg/kg. Through measuring intracellular reactive oxygen species (ROS) and protein carbonyl, assessing the gene expression of tumor suppressor genes (BRCA 1 & 2, TP53), and conducting histopathological analysis, the suppressive effect of Chia oil nanocapsules was examined.ResultsThe increase in ROS and PC levels brought on by DMBA was significantly decreased by the administration of Chia oil nanocapsules. In tumor tissue from rats given Chia oil nanocapsules, the mRNA expression levels of BRCA1, BRCA2, and TP53 were controlled Histopathological analysis clarified that the tissue architecture of breast tumors was improved by nanocapsules management.ConclusionsThese findings demonstrate the ability of Chia oil nanocapsules to inhibit cancer cells in the rat breast.

Heterogeneous Nuclear Ribonucleoprotein K Is Involved in the Estrogen-Signaling Pathway

Heterogeneous nuclear ribonucleoprotein K (hnRNPK) has been found in the nucleus, cytoplasm, and mitochondria. It is implicated in chromatin remodeling, transcription, splicing, and translation processes. Although hnRNPK has reportedly been associated with poor prognosis in colon cancer patients, it is beneficial in gastric cancer as it inhibits cancer cell proliferation. Expression of hnRNPK in ER (Estrogen receptor) -positive/PR (Progesterone receptor) -positive breast cancer was higher than other subtypes; however, the biological functions of hnRNPK in the ER-mediated signaling pathway have not been identified. In this study, we investigated the functions of hnRNPK in the estrogen-signaling pathway. We initially evaluated hnRNPK expression upon treatment with estradiol (E2) and ICI 182,780 in ERα-positive breast cancer cell line MCF-7. This initial evaluation revealed that expression of hnRNPK was increased by E2 treatment but decreased by ICI 182,780 treatment. We further evaluated the effects of estrogen-signaling pathway in hnRNPK knockdown MCF-7 cells using siRNA, which revealed that hnRNPK knockdown decreased ERα expressions and ERα target gene TFF1 by E2 treatment. In addition, we examined the interaction between hnRNPK and ERα because hnRNPK has been reported to interact with several other proteins. These interactions were detected using immunoprecipitation and proximity ligation assay. We then immunolocalized hnRNPK in breast cancer and endometrial cancer. hnRNPK expression was significantly higher in ERα-positive cancer cells in both breast and endometrial cancers. In contrast, hnRNPK expression was significantly lower in Ki-67-positive breast cancer while being significantly higher in Ki-67-positive endometrial cancer. hnRNPK has been found to function differently, depending on the type of cancer (breast or endometrial) that it is expressed in. However, further studies are required to clarify the clinical significance of hnRNPK in breast and endometrial cancer patients.

Abstract P6-02-08: SUV max of 18F FDG-PET/CT: A predictive factor associated with pathologic complete response in luminal HER2–negative breast cancer patients (receiving neoadjuvant chemotherapy)

Abstract Purpose Neoadjuvant chemotherapy (NAC) is considered to be the standard of care for locally advanced breast cancer. When pathological complete response (pCR) is obtained with NAC it is a predictor of better outcome and often used as a surrogate for survival. However, response to NAC of luminal type breast cancer is variable and mostly limited. This study investigated the predictive relevance of several clinicopathological factors, including parameters of 18F FDG-PET/CT, on the pCR to NAC in patients with luminal HER2–negative breast cancer. Methods From 2009 to 2015, 117 hormone receptor-positive, HER2-negative breast cancer patients who were treated with NAC followed by curative surgery at the Kyungpook National University Hospital (Daegu, Korea) were retrospectively analyzed. pCR was defined as the absence of cancer cells in breast and axillary node. 18F FDG-PET/CT maximum standardized uptake value (SUV max) was measured at baseline. Patients received from 6 to 8 cycles of anthracycline-based and taxane-based NAC. Results The median age of the patients was 48 years (range-29-68 years). 104 patients (88.9%) were PR-positive, and forty-nine (41.9%) patients showed high ki-67 expression at initial diagnosis. After NAC, nine patients (7.7%) achieved pCR and patients who had high initial SUV max (≥ 9.09) achieved improved pCR rate compared to low initial SUV max (< 9.09) patients (77.8 % vs. 22.2%). Conclusion In luminal HER2-negative breast cancer, 18F FDG-PET/CT SUV max was useful for predicting pathologic complete response after NAC Table 1Characteristics of study populationMedian, range48 (29-68)Initial clinical T stage 1 2 3 48 (6.8) 83 (70.9) 19 (16.2) 7 (6.0)Initial clinical N stage 0 1 2 310 (8.5) 49 (41.9) 47 (40.2) 11 (9.4)Initial ER expression Negative (0-2) Weak (3-5) Strong (6-8)8 (6.8) 14 (12) 95 (81.2)Initial PR expression Negative (0-2) Weak (3-5) Strong (6-8)13 (11.1) 20 (17.1) 84 (71.8)Initial Ki-67 expression <14% ≥14% Not assessed55 (47) 49 (41.9) 13 (11.1)Pathologic T stage 0 I II III16 (13.7) 50 (42.7) 42 (35.9) 9 (7.7)Pathologic Stage (AJCC) pCR 1A 1B 2A 2B 3A 3C9 (7.7) 23 (19.7) 7 (6.0) 27 (23.1) 21 (17.9) 23 (19.7) 7 (6.0)Histologic grade 1 2 322 (18.8) 61 (52.1) 14 (12)Nuclear Grade 1 2 316 (13.7) 9 (7.7) 50 942.7)Pathologic complete response Yes9 (7.7)Recurrence18 (15.4)Death10 (8.5)table 2Association between pathologic complete response and clinicopathologic featuresFactorsPathologic CR NoPathologic CR YesP- valueAll patients108 (92.3)9 (7.7) Age <40 40-55 56-7016 (18.2) 54(61.4) 18 (20.5)2 (22.2) 6 (66.7) 1 (11.1)0.789Initial clinical T stage 1 2 3 48 (7.4) 76 (70.4) 7 (6.5) 17 (15.7)0 (0) 7 (77.8) 2 (22.2) 0 (0)0.676Initial ER expression Negative (0-2) Weak (3-5) Strong (6-8)7 (6.5) 12 (11.1) 89 (8.4)1 (11.1) 2 (22.2) 6 (66.7)0.504Initial PR expression Negative (0-2) Weak (3-5) Strong (6-8)11 (10.2) 20 (18.5) 77 (71.3)2 (22.2) 0 (0) 7 (77.8)0.247Initial Ki-67 expression <14% ≥14%52 (54.7) 43 (45.3)3 (33.3) 6 (66.7)0.301SUV max (tumor) < 9.09 ≥ 9.0972 (66.7) 36 (33.3)2 (22.2) 7 (77.8)0.012SUV max (axilla) < 6.08 ≥ 6.0858 (67.4) 28 (32.6)3 (42.9) 4 (57.1)0.228 Citation Format: Lee IH, Lee SJ, Lee J, Lee RK, Jung J, Park H, Lee S-w, Chae YS. SUV max of 18F FDG-PET/CT: A predictive factor associated with pathologic complete response in luminal HER2–negative breast cancer patients (receiving neoadjuvant chemotherapy) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-02-08.

CXCR4 EXPRESSION IN DIFFERENT SUBSETS OF CTCs AND SINGLE (DETACHED) BREAST CANCER CELLS

The aim of this study was to assess CXCR4 expression in different subsets of CTCs and single (detached) breast cancer cells.Materials and methods. Thirty five patients with invasive breast carcinoma of no specialtype (IC NST) (T1-4N0-2M0), between 29 and 69 years of age were included in this study. Different subsets of CTCs with CXCR4 expression were evaluated by flow cytometry. A confocal microscopy was used to assess CXCR4 expression in different subsets of single (detached) cancer cells in breast tissue.Results. The CXCR4 was expressed in CTCs without stem-like and EMT phenotype, in CTCs with EMT but not stem markers and in stem-like CTCs without EMT features. In all blood samples, the CXCR4 expression in CTCs with stem-like and EMT phenotype was absent. In breast tumor the CXCR4 was expressed in the non stemlike single (detached) breast cancer cells with EMT features, in the single (detached) breast cancer cells with stem and EMT features. In all tumor samples the stem-like or non stem-like single (detached) breast cancer cells without EMT features were absent.Conclusions. Different subsets of the CTCs exhibited CXCR4. The CXCR4 expression did not depend on the presence or absence of stem or/and EMT features in tumor cells. We showed that some subsets of single (detached) breast cancer cells in the primary tumor were characterized by the ability to express CXCR4 and may be a source of the respective CTC subsets.

Photonic Crystal Fiber-Based Refractive Index Sensor for Early Detection of Cancer

This paper proposes a novel cancer sensor based on dual core photonic crystal fiber for the detection of cancer cells in cervical, breast, and basal parts. The samples are taken in fluid form and infiltrated into the farmed cavity using selective infiltration method. Each fluid form has its own refractive index values which give the various responses in the transmission and loss spectrum. The spectral shift is obtained by inducing the coupling mechanism between silica core and cancer cell core for its launching input optical field which is investigated by finite element method. The proposed structure is also optimized with its structural dimensional property for enhancing the sensitivity. The sensing performances for the cervical cancer cell are obtained as high as 7916 nm/RIU for x-polarization and 10625 nm/RIU for y-polarization with the detection limit of 0.024. The sensitivity to breast cancer cells for xand y-polarization is 5714.28 and 7857.14 nm/RIU, respectively, with detection limit of 0.014. Similarly, the sensitivity to basal cells can also reach 4500 nm/RIU for x-polarization and 6000 nm/RIU for y-polarization. To the best of our knowledge, such sensitivities are the highest reported thus so far.

Proteasome inhibitors modulate anticancer and anti-proliferative properties via NF-kB signaling, and ubiquitin-proteasome pathways in cancer cell lines of different organs

BackgroundCancer is second most common cause of death in the United State. There are over 100 different types of cancer associated with different human organs, predominantly breast, liver, pancreas, prostate, colon, rectum, lung, and stomach. We have recently reported properties of pro-inflammatory (for treatment of various types of cancers), and anti-inflammatory (for cardiovascular disease and diabetes) compounds. The major problem associated with development of anticancer drugs is their lack of solubility in aqueous solutions and severe side effects in cancer patients. Therefore, the present study was carried out to check anticancer properties of selected compounds, mostly aqueous soluble, in cancer cell lines from different organs.MethodsThe anticancer properties, anti-proliferative, and pro-apoptotic activity of novel naturally occurring or FDA approved, nontoxic, proteasome inhibitors/activators were compared. In addition to that, effect of δ-tocotrienol on expression of proteasome subunits (X, Y, Z, LMP7, LMP2, LMP10), ICAM-1, VCAM-1, and TNF-α using total RNAs derived from plasmas of hepatitis C patients was investigated.ResultsOur data demonstrated that following compounds are very effective in inducing apoptosis of cancer cells: Thiostrepton, dexamethasone, 2-methoxyestradiol, δ-tocotrienol, quercetin, amiloride, and quinine sulfate have significant anti-proliferation properties in Hela cells (44% - 87%) with doses of 2.5–20 μM, compared to respective controls. Anti-proliferation properties of thiostrepton, 2-methoxyestradiol, δ-tocotrienol, and quercetin were 70% - 92%. However, thiostrepton, dexamethasone, 2-methoxyestradiol, δ-tocotrienol, quercetin, and quinine sulphate were effective in pancreatic, prostate, breast, lungs, melanoma, Β-lymphocytes, and T-cells (Jurkat: 40% to 95%) compared to respective controls. In lung cancer cells, these compounds were effective between 5 and 40 μM. The IC50 values of anti-proliferation properties of thiostrepton in most of these cell lines were between doses of 2.5–5 μM, dexamethasone 2.5–20 μM, 2-methoxyestradiol 2.5–10 μM, δ-tocotrienol 2.5–20 μM, quercetin 10–40 μM, and (−) Corey lactone 40–80 μM. In hepatitis C patients, δ-tocotrienol treatment resulted in significant decrease in the expression of pro-inflammatory cytokines.ConclusionsThese data demonstrate effectiveness of several natural-occurring compounds with anti-proliferative properties against cancer cells of several organs of humans. Thiostrepton, dexamethasone, 2-methoxyestradiol, δ-tocotrienol and quercetin are very effective for apoptosis of cancer cells in liver, pancreas, prostate, breast, lung, melanoma, Β-lymphocytes and T-cells. The results have provided an opportunity to test these compounds either individually or in combination as dietary supplements in humans for treatment of various types of cancers.

Predictive Factors and Value of ypN+ after Neoadjuvant Chemotherapy in Clinically Lymph Node-Negative Breast Cancer.

BackgroundPathological complete response (pCR) with neoadjuvant chemotherapy (NAC) has been regarded as a surrogate endpoint for disease-free survival (DFS) and overall survival (OS) of patients with breast cancer. No consensus regarding the definition of pCR has been established; there are several definitions according to a variety of classifications. Eradication of cancer cells in both breast and lymph nodes has been better associated with improved prognosis than in the breast alone. Even in patients diagnosed as having clinically node-negative cancer before NAC, postoperative pathological examination often shows axillary lymph node metastases.Patients and MethodsOf the 771 patients with breast cancer who underwent NAC in the Cancer Institute Hospital between January 2000 and May 2009, 146 patients preoperatively diagnosed as having node-negative breast cancer were retrospectively evaluated. We have made the definition of clinically lymph node-negative (N0) as follows: first, ultrasonography before NAC did not show any lymphadenopathy. Second, a cytological procedure confirmed negative study for each patient when ultrasonography suggested lymphadenopathy.ResultsThe median observation period was 79.7 months, and the median age of the subjects was 51 years. Pathological examination at the time of the surgery showed lymph node metastases (ypN+) in 46 patients (31.5%). Histological therapeutic effects revealed ypT0/is in 9 patients (6.2%) and ypTinv in 137 (93.8%). Multivariate analysis demonstrated that younger age (49>), large tumor size, NG3, and ypN+ were significant poor prognostic factors for DFS (p = 0.020, p = 0.008, P = 0.022 and p = 0.010, respectively). Moreover, ypN+ was the only significant poor prognostic factor for OS (p = 0.022). The predictive factors of ypN+ in clinically lymph node–negative breast cancer were ypTinv (p = 0.036) and the luminal type (HR+ and HER2-) (p = 0.029).ConclusionThe prognosis of clinically lymph node negative breast cancer depended on ypN+, which was associated with ypTinv and luminal subtype.

Absence of primary cilia in cell cycle‐arrested human breast cancer cells

Previous studies using cultured cells showed that primary cilia are present in quiescent cells, but are absent in proliferating cells. We studied here the relationship between the presence or absence of primary cilia and the cell cycle arrest of normal epithelial cells and cancer cells in the human normal breast and breast cancer tissues. In normal breast tissues, although most epithelial cells were nonproliferating as estimated by the immunofluorescence staining of the proliferation marker Ki-67, primary cilia were present only in 20-40% of the epithelial cells. In breast cancer tissues, primary cilia were not observed in any of the breast cancer cells. Furthermore, primary cilia were hardly observed in the nonproliferating cancer cells in the orthotopic and metastatic human breast cancer xenograft tumors in mice. These results indicate that the absence of primary cilia does not necessarily represent the proliferating phases of normal epithelial cells and cancer cells.

Reconstruction of the natural history of metastatic cancer and assessment of the effects of surgery: Gompertzian growth of the primary tumor

This work deals with retrospective reconstruction of the individual natural history of solid cancer and assessment of the effects of treatment on metastatic progression. This is achieved through a mathematical model of cancer progression accounting for the growth of the primary tumor, shedding of metastases, their dormancy and growth at secondary sites. To describe dynamics of the primary tumor, we used the Gompertz law, a parsimonious model of tumor growth accounting for its saturation. Parameters of the model were estimated from the age and volume of the primary tumor at surgery and volumes of detectable bone metastases collected from one breast cancer patient and one prostate cancer patient. This allowed us to estimate, for each patient, the ages at cancer onset and inception of all detected metastases, the expected metastasis latency time, parameters of the Gompertzian growth of the primary tumor, and the rates of growth of metastases before and after surgery. We found that for both patients: (1) onset of metastasis occurred when primary tumor was undetectable; (2) inception of all surveyed metastases except one occurred before surgery; and most importantly, (3) resection of the primary tumor led to a dramatic increase in the rate of growth of metastases. The model provides an excellent fit to the observed volumes of bone metastases in both patients. Our results agree well with those obtained previously based on exponential growth of the primary tumor, which serves as model validation. Our findings support the notion of metastatic dormancy and indirectly confirm the existence of stem-like cancer cells in breast and prostate tumors. We also explored the logistic law of primary tumor growth; however, it degenerated into the exponential law for both patients analyzed. The conclusions of this work are supported by a vast body of experimental, clinical and epidemiological knowledge accumulated over the last century.

Potential utility of early metabolic response by 18F-2-fluoro-2-deoxy-d-glucose-positron emission tomography/computed tomography in a selected group of breast cancer patients receiving preoperative chemotherapy

IntroductionTo assess 18F-2-fluoro-2-deoxy-d-glucose-positron emission tomography/computed tomography’s (18F-FDG-PET/CT) potential clinical utility to allow early treatment changes during preoperative chemotherapy (PCT) in patients with early/locally advanced breast cancer (BC). Patients and methodsSixty newly diagnosed early/locally advanced BC patients received 6–8cycles of PCT. Optimal pathologic response (pR) was the absence of cancer cells in breast and axillary lymph nodes. All other conditions were defined as pathologic non-response (pNR). 18F-FDG-PET/CT maximum standardised uptake value (SUVmax) was measured at baseline and after 2cycles of PCT. Metabolic response was defined as SUVmax percentage changes (Δ-SUV) >50% and was compared with pR rates. ResultsThirteen (22%) patients achieved pR; according to immunohistochemistry, 16% of ER-positive/HER2-negative patients, 29% and 27% of HER2-positive and triple negative patients respectively achieved pR. 18F-FDG-PET/CT showed the highest specificity (38%) and negative predictive value (100%) in ER-positive/HER2-negative patients. In this subgroup, at a median follow-up of 36.6months, median disease-free survival was still not reached in metabolic responders while it was 37months in metabolic non-responders (p=0.049). DiscussionEarly metabolic non-response was always associated to pNR and poor prognosis in ER-positive/HER2-negative patients. In this subgroup, 18F-FDG-PET/CT might be useful to select patients who will probably benefit from early therapeutic strategy modifications.

Abstract P1-05-14: Multiscale computational modeling of breast cancer invasion: Towards a predictive patient-based tool

Abstract Background: Understanding the mechanisms of the growth and spread of cancer cells in the human breast and providing effective treatment continues to remain a significant challenge. Cancer cell invasion of breast tissue plays a pivotal role in the metastatic cascade through complex, coupled dynamics of the constituent processes occurring over a range of spatial and temporal scales, ranging from genetic events through intracellular signaling pathways through cell-matrix interactions to tissue scale changes. Method: While most previous computational modeling has been carried out at the level of a single spatial or temporal scale, the work presented here has developed a novel multiscale modeling and computational simulation framework. Formulated in both two and three spatial dimensions, this approach is based on a new type of multiscale moving boundary computational model that explores the crucial role that matrix degrading enzymes, secreted by individual cancer cells (micro-scale) along the invasive edge of the tumour, play in the overall dynamics of the tissue-scale invasion (macro-scale). Results: The computational simulation results we have obtained reveal a rich variety of cancer invasion patterns that emerge in the vicinity of a primary breast cancer. In the presence of heterogeneous tissue, our computational simulation results show well-defined “lobular” and “fingering” invasion patterns, consistent with the spread of a breast carcinoma, and which remain robust with respect to any changes made in the model parameters. These patterns are found to be compatible with respect to both the dynamic heterogeneity of cancer cell macro-scale distributions and to the evolution of the heterogeneity of the surrounding breast tissue. Conclusions: By exploring the dynamics of the molecular processes of matrix degrading enzymes and of tissue-scale spatio-temporal cancer tissue evolution, this novel multiscale computational modeling framework faithfully replicates the cancer invasion process. Development of this computational tool should allow pre-operative breast cancer patient data to be used to predict the extent of breast cancer invasion and hence the extent of surgical resection. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-05-14.

Targeting TCTP as a New Therapeutic Strategy in Castration-resistant Prostate Cancer

Heat shock protein 27 (Hsp27) is highly overexpressed in castration-resistant prostate cancer (CRPC) and an antisense inhibitor (OGX-427) is currently in phase II clinical trials. In order to understand mechanisms of action of Hsp27 and find new therapeutic targets specific of CRPC, we screened for Hsp27 client proteins. Here, we report that translationally controlled tumor protein (TCTP) is a new Hsp27 client protein involved in Hsp27 cytoprotection. We found that TCTP expression is absent or weak in normal prostate cells, moderately expressed in 18.5% of treatment naive PC, and becomes uniformly and strongly expressed in 75% of CRPC. To define TCTP function, we developed and worldwide patented a TCTP antisense oligonucleotide (ASO). Interestingly, we found that CRPC progression correlates with TCTP overexpression and loss of P53. TCTP knockdown restored P53 expression and function, suggesting that castration-sensitivity is directly linked to P53 expression. Collectively, these findings provide a new Hsp27 cytoprotection mechanism in CRPC, and preclinical proof-of-concept that combining ASO-mediated TCTP knockdown with castration and/or docetaxel therapy could serve as a novel strategy to treat CRPC, with no or little toxicity for normal prostate cells.

362P - Might Early Metabolic Response by 18F-FDG-PET/CT be Useful to Select Patients (PTS) With Breast Cancer (BC) who Will not Optimally Respond to Preoperative Chemotherapy (PCT)?

ABSTRACT Purpose To evaluate 18F-2-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) changes between baseline and after 2 cycles of PCT in pts with early/locally advanced (E/LA) BC, with the aim to verify whether early metabolic assessment of response during PCT may have a role in clinical practice to enable early changes in the therapeutic strategy. Patients and methods Sixty pts with newly diagnosed E/LA BC received 6-8 cycles of anthracycline and taxane-based PCT. Fifty-eight pts underwent surgery, which consisted in breast conserving surgery or radical mastectomy; axillary node dissection was performed in all cases. Optimal pathologic response (pR) to PCT was defined as absence of cancer cells in breast and ipsilateral axillary lymph nodes. All other conditions were defined as nonresponders (pNR). Maximum standardized uptake value (SUV max) with 18F-FDG PET/CT was measured for each pathologic lesion at baseline and after 2 cycles of PCT. SUV max percentage changes (Δ-SUV) were compared with pR rate according to immunohistochemical (IHC) BC characteristics. Δ-SUV >50% defined a metabolic response (MetR). Results Thirteen (22%) of 60 pts achieved pR. According to IHC, pR rates where 16% in ERpositive/HER2negative (ER + /HER2-) pts, 29% and 27% in HER2-positive (HER2+) and triple negative (TN) pts respectively. Sensitivity of metR to identify pR was 100% in all three subgroups, but the specificity was low: 38% in ER + /HER2- pts (38%) was the highest value. In this subgroup of pts PET had a low positive predictive value (24%), while the negative predictive value was 100%, showing, compared to HER2+ and TN pts, the highest ability to correctly predict pNR (32%). At a median follow-up of 36.6 months, recurrence rate was higher in metabolic non-responders, particularly in the ER + /HER2- subgroup, in which Kaplan-Meier analysis of disease-free survival confirmed a significant difference (p = 0.0490). Conclusions PET assay after 2 cycles of PCT correctly predicted pNR in 32% of ER + /HER2- pts, identifying a subgroup of BC pts with worse prognosis who might benefit from an early change of the therapeutic strategy. Disclosure All authors have declared no conflicts of interest.