Hallmark Of Breast Cancer Research Articles

Abstract 2371: Multi-cell phylogenetic inference of copy number evolution in breast cancer

Abstract Aneuploidy is a hallmark of breast cancer, but little is known about how these complex genomic rearrangements evolve during tumor growth. To investigate this question, we developed a Highly-Multiplexed Single Nucleus Sequencing (HM-SMS) method to profile genome-wide copy number in individual tumor cells and compared multiple cells to infer evolutionary lineages. We applied this method to analyze thousands of single cells from 12 triple-negative breast cancer patients and 10 ductal-carcinoma-in-situ (DCIS) patients. Integer copy number profiles were calculated from a combination of sequencing data and ploidy estimation using flow cytometry. A multi-cell segmentation algorithm was used to identify common CNA events that are shared between tumor cells in each patient. Trinary event matrices were calculated for each patient to determine the presence or absence of individual copy number aberrations (CNAs) in individual cells. Using the maximum parsimony criterion, we inferred a phylogenetic tree for each tumor and estimated the temporal order of the CNAs.. Our data suggest that most tumors consisted of 1-4 major clonal subpopulations that shared a common evolutionary lineage, suggesting that they evolved from a single normal cell in the breast tissue. Furthermore our data support a punctuated model of copy number evolution, which which the majority of CNAs were acquired in a short evolutionary burst, followed by one or more stable clonal expansions to form the tumor mass. Citation Format: Alexander J. Davis, Ruli Gao, Emi Sei, Pei-Ching Tsai, Anna Casasent, Amy Zhang, Xiuqing Shi, Yong Wang, Jill Waters, Funda Meric-Bernstam, Mary Edgerton, Nicholas Navin. Multi-cell phylogenetic inference of copy number evolution in breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2371.

Abstract LB-154: Epigenetic silencing of triple-negative breast cancer hallmarks by Withaferin A

Abstract Background: Triple negative breast cancer (TNBC) is characterized by poor prognosis and a DNA hypomethylation profile. We found that the steroidal lactone Withaferin A (WA), isolated from the plant Withania somnifera, triggers active chromatin remodeling and elicits promising chemosensitizing effects in triple negative breast cancer (BC) cells. Here, we have further characterized potential involvement of epigenetic reprogramming by Withaferin A in TNBC treatment. Materials and methods: By Infinium HumanMethylation450 arrays, Epityper Mass array and CpG pyrosequencing, we determined genome-wide DNA methylation changes in weakly-metastatic and aggressive, metastatic BC cell lines treated with a pharmacologically relevant concentration of 700 nM WA. In parallel, we performed ChIP analysis of histone mark H3K4Me3 to evaluate histone demethylation by JARID1B/KDM5B. Furthermore, epigenetic changes in response to WA were crosscompared with genomewide methylation changes and clinical breast cancer patient characteristics in The Cancer Genome Atlas database. Results: In contrast to the DNA hypomethylating agent 5-aza-2’-deoxycytidine (DAC), WA treatment of TNBC cells silences an epigenetic cancer network through gene-specific hypermethylation of tumor promoting genes including ADAM metallopeptidase domain 8 (ADAM8), urokinase-type plasminogen activator (PLAU), tumor necrosis factor (ligand) superfamily, member 12 (TNFSF12), and genes related to detoxification (glutathione S-transferase mu 1, GSTM1), or mitochondrial metabolism (malic enzyme 3, ME3). Remarkably, DNA hypermethylation of corresponding CpG sites in these genes correlates with receptor tyrosine-protein kinase erbB-2 amplification (HER2)/estrogen receptor (ER)/progesterone receptor (PR) positive status in primary BC tumors. Increased expression levels of JARID1B, promoter-specific loss of active H3K4me3 chromatin marks and gain of DNA methylation suggest that WA-specific gene silencing involves epigenetic reprogramming of HER2/ER/PR-dependent gene expression programs to suppress aggressive TNBC characteristics in favor of luminal BC hallmarks with an improved therapeutic sensitivity. Conclusions: WA may represent a novel and attractive phytopharmaceutical to overcome therapy resistance in TNBC. Citation Format: Wim Vanden Berghe, Katarzyna Szarc vel Szic, Ken Declerck, René A.J. Crans, Jolien Diddens, Clarissa Gerhäuser. Epigenetic silencing of triple-negative breast cancer hallmarks by Withaferin A. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-154.

Decreased Usage of Specific Scrib Exons Defines a More Malignant Phenotype of Breast Cancer With Worsened Survival

SCRIB is a polarity regulator known to be abnormally expressed in cancer at the protein level. Here we report that, in breast cancer, an additional and hidden dimension of deregulations exists: an unexpected SCRIB exon usage pattern appears to mark a more malignant tumor phenotype and significantly correlates with survival. Conserved exons encoding the leucine-rich repeats tend to be overexpressed while others are underused. Mechanistic studies revealed that the underused exons encode part of the protein necessary for interaction with Vimentin and Numa1, a protein which is required for proper positioning of the mitotic spindle. Thus, the inclusion/exclusion of specific SCRIB exons is a mechanistic hallmark of breast cancer, which could potentially be exploited to develop more efficient diagnostics and therapies.

Estrogen Receptor Expression Is Associated with DNA Repair Capacity in Breast Cancer.

Estrogen-receptor-positive (ER+) tumors employ complex signaling that engages in crosstalk with multiple pathways through genomic and non-genomic regulation. A greater understanding of these pathways is important for developing improved biomarkers that can better determine treatment choices, risk of recurrence and cancer progression. Deficiencies in DNA repair capacity (DRC) is a hallmark of breast cancer (BC); therefore, in this work we tested whether ER signaling influences DRC. We analyzed the association between ER positivity (% receptor activation) and DRC in 270 BC patients, then further stratified our analysis by HER2 receptor status. Our results show that among HER2 negative, the likelihood of having low DRC values among ER- women is 1.92 (95% CI: 1.03, 3.57) times the likelihood of having low DRC values among ER+ women, even adjusting for different potential confounders (p<0.05); however, a contrary pattern was observed among HER2 positives women. In conclusion, there is an association between DRC levels and ER status, and this association is modified by HER2 receptor status. Adding a DNA repair capacity test to hormone receptor testing may provide new information on defective DNA repair phenotypes, which could better stratify BC patients who have ER+ tumors. ER+/HER2- tumors are heterogeneous, incompletely defined, and clinically challenging to treat; the addition of a DRC test could better characterize and classify these patients as well as help clinicians select optimal therapies, which could improve outcomes and reduce recurrences.

Abstract 1972: LIN28 gene targets are key mediators of breast cancer disease processes

Abstract LIN28 is an evolutionally conserved RNA-binding protein with critical functions in developmental timing, pluripotency and reprogramming. At the molecular level, most studies indicate that LIN28 modulates gene networks and biological processes by negatively regulating miRNA biogenesis and post-transcriptionally regulating mRNA translation. In addition, increasing evidence suggests that LIN28 is an oncogene, promoting cell growth in various cancers, including breast cancer; however the molecular mechanisms underlying these effects are not known. To provide mechanistic insights into how LIN28 modulates the gene networks that control breast cancer disease processes, we integrate next generation technologies, biochemical approaches and computational analysis to identify LIN28 mRNA targets. Our results demonstrated that endogenous LIN28 binds 843 mRNAs, ∼3.5% of the total human reference genome in breast cancer cells. Gene ontology analyses reveal that the genes targeted by LIN28 are enriched in those that control cell metabolism. Furthermore, using proteomics analysis, we identify heteronuclear ribonucleoprotein A1 (hnRNP A1), a protein with multiple roles in mRNA metabolism, as a LIN28 interacting partner. Importantly, hnRNP A1 is overexpressed and linked to increased cell proliferation and transformation in a wide variety of cancers, including breast cancer. Moreover, and consistent with the observation that majority of mRNAs bound by LIN28 are involved in metabolism, hnRNP A1 is known to regulate the expression of key enzymes that control metabolism in cancer cells. In-depth analysis of the transcriptomes of LIN28 and hNRNPA1 siRNA-treated cells reveal that these two proteins cooperate to regulate alternative splicing and the steady state mRNA expression of genes implicated in various aspects of breast cancer biology. Most notably, depleting LIN28 results in differential isoform expression of the ENAH gene, which is linked to breast cancer metastasis. In summary, by integrating genomic, biochemical and computational approaches, we identify a broad network of LIN28 targets that modulate cancer cell metabolism, cancer cell invasiveness and the immune response, processes that are hallmarks of breast cancer. Citation Format: Harriet K. Kinyamu, Jun Yang, Brian Bennett, Sara Grimm, Pierre Bushel, Trevor Archer. LIN28 gene targets are key mediators of breast cancer disease processes. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1972. doi:10.1158/1538-7445.AM2015-1972

Abstract P5-08-02: Inhibition of CDK4/6 induces senescence and autophagy in ER positive breast cancers

Abstract Deregulation of the cell cycle machinery is a hallmark of breast cancer, facilitating aberrant proliferation that fuels tumorigenesis and disease progression. This makes the cell cycle, particularly the cyclin dependent kinases (CDKs) an ideal choice for drug targeting in these tumors. Palbociclib or PD0332991, a potent CDK4/6 inhibitor is a known anti-proliferative agent that induces G1 arrest and prevents tumor growth in several cancers including ER+ breast cancer. This drug has shown tremendous success in Phase II clinical trials in ER+ breast cancers and is presently undergoing phase III trials in combination with letrazole. However, little is know about its precise mechanism of action and modes of resistance in ER+ breast cancers. This is critical in understanding the biology of treatment response, drug resistance and combination strategies, and this project aims at addressing these gaps in knowledge. We have used a series of ER+ breast cancer cell lines to examine the mechanism of action of Palbociclib and identify the nodes that could mediate resistance to this agent. Our results have revealed that continuous treatment of ER+ breast cancer cells with Palbociclib results in a G1 arrest with concomitant downregulation of pRb. Treated cells undergo senescence and autophagy, but not apoptosis. Further, we have shown that the induction of quiescence or senescence and autophagy occurs in a time and dose dependent manner. Since this agent is known to be a specific CDK4/6 inhibitor, we next downregulated these kinases in our model system and subjected them to Palbociclib treatment. Interestingly, downregulation of CDK4 or CDK6 did not significantly alter the sensitivity of these cells to the anti-tumor effects of Palbociclib. Next we asked if depletion of Rb can render the cells resistant to Palbociclib. Results revealed that the complete depletion of Rb was sufficient to reduce the sensitivity of ER+ cells to Palbociclib by 4-6 fold. However, the very steep pattern of the growth response curves suggest that in the absence of Rb, Palbociclib can effectively inhibit another target, albeit, at a higher drug concentration. Lastly, to interrogate if deregulation of the G1/S checkpoint can render cells more resistant to this inhibitor, we examined if overexpression of the low molecular weight isoforms of Cyclin-E (LMW-E), which by themselves are sufficient to induce an oncogenic phenotype through constitutive phosphorylation of Rb, can mediate resistance in these cells. These results, which were similar to those from the Rb knockout studies, revealed that LMW-E overexpression can reduce the sensitivity of ER+ breast cancer cells to Palbociclib by 5-7 fold. Collectively, our studies suggest that inhibition of G1/S transition is not the sole mode of action of Palbociclib and that there is another unidentified target, which is specifically inhibited by this agent, when the G1/S check point is compromised. Since the deregulation of the G1/S checkpoint is likely to occur clinically in patients treated with Palbociclib, identification of this second target will be instrumental in efforts to overcome resistance and identify biomarkers of sensitivity to this agent in breast cancer patients. Citation Format: Smruthi Vijayaraghavan, Khandan Keyomarsi. Inhibition of CDK4/6 induces senescence and autophagy in ER positive breast cancers [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-08-02.

MicroRNAs in breast cancer: regulatory roles governing the hallmarks of cancer

A large number of etiological factors and the complexity of breast cancers present challenges for prevention and treatment. Recently, the emergence of microRNAs (miRNAs) as cancer biomarkers has added an extra dimension to the 'molecular signatures' of breast cancer. Bioinformatic analyses indicate that each miRNA can regulate hundreds of target genes and could serve functionally as 'oncogenes' or 'tumour suppressor' genes, and co-ordinate multiple cellular processes relevant to cancer progression. A number of studies have shown that miRNAs play important roles in breast tumorigenesis, metastasis, proliferation and differentiation of breast cancer cells. This review provides a comprehensive overview of miRNAs with established functional relevance in breast cancer, their established target genes and resulting cellular phenotype. The role and application of circulating miRNAs in breast cancer is also discussed. Furthermore, we summarize the role of miRNAs in the hallmarks of breast cancer, as well as the possibility of using miRNAs as potential biomarkers for detection of breast cancer.

Dual MMP7-proximity-activated and folate receptor-targeted nanoparticles for siRNA delivery.

A dual-targeted siRNA nanocarrier has been synthesized and validated that is selectively activated in environments where there is colocalization of two breast cancer hallmarks, elevated matrix metalloproteinase (MMP) activity and folate receptor overexpression. This siRNA nanocarrier is self-assembled from two polymers containing the same pH-responsive, endosomolytic core-forming block but varying hydrophilic, corona-forming blocks. The corona block of one polymer consists of a 2 kDa PEG attached to a terminal folic acid (FA); the second polymer contains a larger (Y-shaped, 20 kDa) PEG attached to the core block by a proximity-activated targeting (PAT), MMP7-cleavable peptide. In mixed micelle smart polymer nanoparticles (SPNs) formed from the FA- and PAT-based polymers, the proteolytically removable PEG on the PAT polymers shields nonspecific SPN interactions with cells or proteins. When the PAT element is cleaved within an MMP-rich environment, the PEG shielding is removed, exposing the underlying FA and making it accessible for folate receptor-mediated SPN uptake. Characterization of mixed micelles prepared from these two polymers revealed that uptake and siRNA knockdown bioactivity of a 50% FA/50% PAT formulation was dependent on both proteolytic activation and FA receptor engagement. MMP activation and delivery of this formulation to breast cancer cells expressing the FA receptor achieved greater than 50% protein-level knockdown of a model gene with undetectable cytotoxicity. This modular nanoparticle design represents a new paradigm in cell-selective siRNA delivery and allows for stoichiometric tuning of dual-targeting components to achieve superior targeting specificity.

Association of BCL2L12 overexpression with prolonged disease-free survival in breast cancer.

e22202 Background: Deregulated apoptosis is a hallmark of breast cancer and plays an important role in the pathogenesis and progression of this malignancy. BCL2 gene family members are major regula...

Overexpression of a novel cell cycle regulator ecdysoneless in breast cancer: a marker of poor prognosis in HER2/neu-overexpressing breast cancer patients

Uncontrolled proliferation is one of the hallmarks of breast cancer. We have previously identified the human Ecd protein (human ortholog of Drosophila Ecdysoneless, hereafter called Ecd) as a novel promoter of mammalian cell cycle progression, a function related to its ability to remove the repressive effects of Rb-family tumor suppressors on E2F transcription factors. Given the frequent dysregulation of cell cycle regulatory components in human cancer, we used immunohistochemistry of paraffin-embedded tissues to examine Ecd expression in normal breast tissue versus tissues representing increasing breast cancer progression. Initial studies of a smaller cohort without outcomes information showed that Ecd expression was barely detectable in normal breast tissue and in hyperplasia of breast, but high levels of Ecd were detected in benign breast hyperplasia, ductal carcinoma in situ (DCIS) and infiltrating ductal carcinoma (IDCs) of the breast. In this cohort of 104 IDC patients, Ecd expression levels showed a positive correlation with higher grade (P = 0.04). Further analyses of Ecd expression using a larger, independent cohort (954) confirmed these results, with a strong positive correlation of elevated Ecd expression with higher histological grade (P = 0.013), mitotic index (P = 0.032), and Nottingham Prognostic Index score (P = 0.014). Ecd expression was positively associated with HER2/neu (P = 0.002) overexpression, a known marker of poor prognosis in breast cancer. Significantly, increased Ecd expression showed a strong positive association with shorter breast cancer specific survival (BCSS) (P = 0.008) and disease-free survival (DFS) (P = 0.003) in HER2/neu overexpressing patients. Taken together, our results reveal Ecd as a novel marker for breast cancer progression and show that levels of Ecd expression predict poorer survival in Her2/neu overexpressing breast cancer patients.Electronic supplementary materialThe online version of this article (doi:10.1007/s10549-011-1946-8) contains supplementary material, which is available to authorized users.

Breast Cancer Prognosis and Management: Role of Gene Expression Profiling

Gene expression profiling has shown that molecular heterogeneity is a hallmark of breast cancer. Authors of a recent review present a comprehensive update of the molecular subtypes of breast cancer and their clinical ramifications. Microarray-based analyses first allowed identification of seven intrinsic subgroups of breast cancer (luminal A, …

Breast Cancer among Urban Nigerian Women: Appraising Presentation and the Quality of Care

Introduction: Late presentation is the hallmark of breast cancer among Nigerians. Awareness of the disease is low and care of this condition has not received adequate attention from Government. Health education to improve awareness was intensified in the last 2 decades. This study aims to assess the current state of care and presentation of breast cancer in Lagos, Nigeria. Patients and Methods: A prospective study of 350 breast cancer patients seen over a period of four years at a General Surgical unit out-patient clinic of LASUTH was carried out. Data on patient characteristics, presentation, diagnosis and treatment were obtained and analyzed. Results: Average duration of symptoms was 46.48 weeks. One fifth presented within 3 months while 17% presented after 1 year. Lumps were self-detected in 96% and 287 (82%) presented with advanced disease (stages III & IV). Two hundred and thirty seven patients (67%) received treatment and 175 (74%) among them had mastectomy. None had breast conservation surgery. One hundred and fourteen patients (48%) absconded and did complete treatment. Conclusion: The trend of late presentation has not changed with current efforts to improve breast cancer awareness. Quality of care for our breast cancer patients is not satisfactory and needs improvement.

Breast cancer and spider telangiectasias at diagnosis and its relation to histopathology and prognosis: a population-based study

Angiogenesis is one of the hallmarks of breast cancer. The status of angiogenesis is important in therapy choice. Spider telangiectasias (telangiectasias) may reflect an increased ability to form vessels. Our first aim was to identify patient and tumor characteristics associated with the occurrence of telangiectasias at the time of breast cancer diagnosis. The second aim was to study the overall survival in relation to the occurrence of telangiectasias at the time of breast cancer diagnosis. A standardized questionnaire was used to interview 1682 consecutive breast cancer patients about risk factors between 1980 and 2009. Occurrence of telangiectasias at the time of breast cancer diagnosis on the upper thorax, head, and/or neck was recorded by one physician. In the cohort, 93 women (5.5%) had telangiectasias. Occurrence of telangiectasias was positively associated with weight, odds ratio (OR) 1.02 (95% confidence interval (CI) 1.00-1.05) per kg, ever-use of oral contraceptives OR 2.67(CI 1.55-4.63) and hormone replacement therapy OR 2.68(CI 1.63-4.39), and negatively associated with parity OR 0.45(CI 0.25-0.79). Telangiectasias were not present in patients with comedo breast cancer. Patients with occurrences of telangiectasias diagnosed before the age of 50 had a statistically non-significant worse overall survival, whereas the patients with occurrences of telangiectasias diagnosed at age 50 or after had a statistically significant better overall survival (P interaction = 0.016). The relationship between the occurrence of telangiectasias and the overall survival in the older patient-group was independent of ever-use of HRT. Hormonal risk factors for breast cancer were associated with the occurrence of spider telangiectasias. The occurrence of telangiectasias may reflect the angiogenic status of the tumor. We hypothesize that telangiectasias could be used as selection criteria for anti-angiogenic therapy in younger breast cancer patients. Therefore, patients with comedo breast cancers maybe a group that may benefit less from anti-angiogenic therapy.

High-Resolution Computed Tomography of Single Breast Cancer Microcalcifications in Vivo

Microcalcification is a hallmark of breast cancer and a key diagnostic feature for mammography. We recently described the first robust animal model of breast cancer microcalcification. In this study, we hypothesized that high-resolution computed tomography (CT) could potentially detect the genesis of a single microcalcification in vivo and quantify its growth over time. Using a commercial CT scanner, we systematically optimized acquisition and reconstruction parameters. Two ray-tracing image reconstruction algorithms were tested: a voxel-driven "fast" cone beam algorithm (FCBA) and a detector-driven "exact" cone beam algorithm (ECBA). By optimizing acquisition and reconstruction parameters, we were able to achieve a resolution of 104 μm full width at half-maximum (FWHM). At an optimal detector sampling frequency, the ECBA provided a 28 μm (21%) FWHM improvement in resolution over the FCBA. In vitro, we were able to image a single 300 μm × 100 μm hydroxyapatite crystal. In a syngeneic rat model of breast cancer, we were able to detect the genesis of a single microcalcification in vivo and follow its growth longitudinally over weeks. Taken together, this study provides an in vivo "gold standard" for the development of calcification-specific contrast agents and a model system for studying the mechanism of breast cancer microcalcification.

Adipose progenitor cells increase fibronectin matrix strain and unfolding in breast tumors

Increased stiffness represents a hallmark of breast cancer that has been attributed to the altered physicochemical properties of the extracellular matrix (ECM). However, the role of fibronectin (Fn) in modulating the composition and mechanical properties of the tumor-associated ECM remains unclear. We have utilized a combination of biochemical and physical science tools to evaluate whether paracrine signaling between breast cancer cells and adipose progenitor cells regulates Fn matrix assembly and stiffness enhancement in the tumor stroma. In particular, we utilized fluorescence resonance energy transfer imaging to map the molecular conformation and stiffness of Fn that has been assembled by 3T3-L1 preadipocytes in response to conditioned media from MDA-MB231 breast cancer cells. Our results reveal that soluble factors secreted by tumor cells promote Fn expression, unfolding, and stiffening by adipose progenitor cells and that transforming growth factor-β serves as a soluble cue underlying these changes. In vivo experiments using orthotopic co-transplantation of primary human adipose-derived stem cells and MDA-MB231 into SCID mice support the pathological relevance of our results. Insights gained by these studies advance our understanding of the role of Fn in mammary tumorigenesis and may ultimately lead to improved anti-cancer therapies.

Breast Cancer Knowledge And Screening Practices Among Nigerian Medical Students

Background. Late presentation of patients at advanced stages of disease forms the hallmark of breast cancer in Nigerian women. The peak age of breast cancer presentation among Nigerian women is about 10-15years earlier than what is observed in Caucasian women, where it occurs between the ages of 35-45 years. This study assessed breast cancer knowledge and behavior in terms of screening practices among introductory clinical medical students in Delta State. Nigeria. Materials and Method. The data consisted of selected and constructed response items on a questionnaire which was administered to all introductory clinical (medical) students 18 years and older. Participation in this study was voluntary. The instrument consisted of multiple choice questions that measured variables such as general breast cancer knowledge, risk factors, symptoms, barriers, use of breast cancer screening tests, screening practices, and demographic characteristics. Results. A total of 18 questionnaires were distributed to introductory clinical (medical) students age 18 years and above at the Delta State University in Warri, Nigeria. The response rate was 100%. Age range of respondents was 21-26 years. The overall knowledge of breast cancer was 89.1% while knowledge of the risk factors for breast cancer development was 62.7%. Knowledge of breast cancer symptoms was 67.8%. There were no barriers to breast screening exercises. All the participants admitted performing breast self examination regularly but 22.2% did not know how often breast examination should be done. Three participants (16.7%) have never been told about breast cancer screening by a nurse or physician previously and 16 students (88.9%) have never had a clinical breast examination. Conclusion. While the overall knowledge of breast-cancer, risk factors and performance of breast self examination were good, further studies on a wider scale in Nigeria are needed to elucidate reasons why the elite women do not present themselves for clinical breast examination and why the physicians do not practice routine clinical breast examination.

A Functional Connection between pRB and Transforming Growth Factor β in Growth Inhibition and Mammary Gland Development

Transforming growth factor beta (TGF-beta) is a crucial mediator of breast development, and loss of TGF-beta-induced growth arrest is a hallmark of breast cancer. TGF-beta has been shown to inhibit cyclin-dependent kinase (CDK) activity, which leads to the accumulation of hypophosphorylated pRB. However, unlike other components of TGF-beta cytostatic signaling, pRB is thought to be dispensable for mammary development. Using gene-targeted mice carrying subtle missense changes in pRB (Rb1(DeltaL) and Rb1(NF)), we have discovered that pRB plays a critical role in mammary gland development. In particular, Rb1 mutant female mice have hyperplastic mammary epithelium and defects in nursing due to insensitivity to TGF-beta growth inhibition. In contrast with previous studies that highlighted the inhibition of cyclin/CDK activity by TGF-beta signaling, our experiments revealed that active transcriptional repression of E2F target genes by pRB downstream of CDKs is also a key component of TGF-beta cytostatic signaling. Taken together, our work demonstrates a unique functional connection between pRB and TGF-beta in growth control and mammary gland development.

Knowledge, attitudes and practice of breast cancer screening among female health workers in a Nigerian urban city.

BackgroundLate presentation has been observed as the hallmark of breast cancer in Nigerian women and an earlier onset has been reported in this population. This study was designed to assess the awareness of female health workers about risk factors and screening methods for early detection of breast cancer.MethodsA cross-sectional descriptive study was carried out among female health workers in the two major government health institutions in Benin City, Edo State capital in Nigeria.Data analysis was by SPSS version 10 and test of significance was done with differences considered significant at p < 0.05.ResultsThree hundred and ninety-three (393) female health workers out of five hundred and five eligible subjects completed and returned the questionnaires, giving a response rate of 77.8%. One hundred and two (26%) were Doctors, two hundred and fifty-four (64.6%) Nurses, and thirty-seven (9.4%) were Radiographers, Laboratory Scientists and Pharmacists. A high proportion of our respondents had very poor knowledge about risk factors for breast cancer (55%). The awareness of mammography as a diagnostic method was very high (80.7%), but an extremely low knowledge of mammography as a screening method was found. Mammography practice of only 3.1% was found among those above 40 years of age who qualify for routine annual screening. Relatively low knowledge (45.5%) about Breast Self Examination (BSE) as a screening method was found.ConclusionThese female health workers who are expected to act as role models and educate the public had poor knowledge of risk factors for breast cancer and practice of breast cancer screening. There is very urgent need for regular update courses for health workers concerning breast cancer education including screening methods.

The hallmarks of breast cancer by Raman spectroscopy

This paper presents new biological results on ex vivo breast tissue based on Raman spectroscopy and demonstrates its power as diagnostic tool with the key advantage in breast cancer research. The results presented here demonstrate the ability of Raman spectroscopy to accurately characterize cancer tissue and distinguish between normal, malignant and benign types. The goal of the paper is to develop the diagnostic ability of Raman spectroscopy in order to find an optical marker of cancer in the breast tissue. Applications of Raman spectroscopy in breast cancer research are in the early stages of development in the world. To the best of our knowledge, this paper is one of the most statistically reliable reports (1100 spectra, 99 patients) on Raman spectroscopy-based diagnosis of breast cancers among the world women population.

Biological mechanisms that trigger breast cancer (BC) tumor progression are molecular subtype dependent

10581 Background: We have recently developed several gene expression indices related to hallmarks of breast cancer involving various biological processes such as tumor invasion, impairment of immune response, sustained angiogenesis, evasion of apoptosis and self- sufficiency in growth signal, and investigated their impact on clinical outcome. Here, we aim to refine our biological understanding and the prognostic impact of these indices according to the previously described molecular subtypes based on the estrogen (ER) and ERBB2 receptors. Methods: Each of these indices were developed in a series of 581 BC samples and then computed on several publicly available microarray studies totaling over 2100 BC patients. Multivariate analyses were used to study the dependency patterns between these indices, the molecular subtypes and their impact on survival. Results: ER-/ERBB2- and ERBB2+ subgroups were significantly associated with high expression levels of the proliferation, tumor invasion, angiogenesis and immune response indices. Multivariate analysis showed that in the ER+/ERBB2- subgroup, only tumor size and the proliferation and tumor invasion indices were significantly associated with clinical outcome, with the proliferation index having the largest HR and most significant p-value (HR 3.25; CI 2.31–4.56; p=1.2 10-11). In contrast, in the ER-/ERBB2- subgroup, only tumor size (HR 2.08; CI 1.14–3.81; p=0.01) and immune response index (HR 0.66; CI 0.46–0.95; p=0.02) were associated with prognosis whereas in the ERBB2+ tumors only nodal status (HR 3.40; CI 0.96–12.10; p=0.05) and tumor invasion index (HR 3.03; CI 1.32–6.95; p=0.009) showed significant association with survival. Of interest, proliferation index lost its significance as almost all ER- /ERBB2- and ERBB2 + tumors showed high proliferation levels. Conclusions: Although proliferation seems to be the strongest parameter predicting clinical outcome in ER+/ERBB2- subtype, immune response and tumor invasion appear to be the main molecular mechanisms associated with prognosis in the ER-/ERBB2- and ERBB2+ subgroups respectively. Defining these clinico-genomic models in the specific molecular subgroups will be the key to success for personalized medicine. No significant financial relationships to disclose.