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Introduction: Parous rats treated with chemical carcinogen develop a low incidence of overt mammary cancers compared to that in carcinogen-treated nulliparous rats. Examination of the mammary glands at necropsy 12 months after carcinogen treatment revealed that a high percentage of the parous rats had preneoplastic mammary lesions. These studies demonstrate that in parous rats, initiation of mammary carcinogenesis occurs at a high efficiency, although the systemic and local environment is inadequate for promotion to overt cancers. Stem cells have been implicated as the target cells for tumor initiation. In this study we investigated if parity altered the mammary stem cells. Materials and Methods: Nulliparous and parous parous were euthanized and the preneoplastic mammary lesions were surgically removed under a dissection microscope. The lesions were dissociated using the collagenase digestion method. After digestion the cells were separated using the percoll gradient. The enriched epithelial cell population was cultured and sorted for stem cells using ALDH, CD44, CD24 as markers. Sphere formation assays was established using 5000 cells/well on ultra-low attachment 6-well plates. For self-renewal assay, the 1st generation spheres was dissociated using Accutase, counted and replated in the same media as single cells with a plating density of 5000 cells/well. The same process was followed for the subsequent generations. In another set of experiments stem cells were treated with growth hormone (GH) and prolactin (PRL) to identify the role of these two mammogenic hormones on the mammary stem cells. Using the stem cells we performed the limiting dilution analysis to estimate the tumor forming capacity of the initiated mammary stem cells. Results: The sphere forming capacity of parous mammary stem cells was significantly reduced compared to nulliparous mammary stem cells. In addition, the self-renewing abilities were also remarkably decreased. Treatment with GH and PRL restored the sphere forming and self-renewing capabilities of parous mammary stem cells similar to nulliparous mammary stem cells. Further, the limiting dilution assay also demonstrated that parity altered the mammary stem cells making them less capable of forming tumors. Conclusion: Parity significantly altered the characteristics of the mammary stem cells rendering them to be resistant to mammary tumorigenesis. GH and PRL were able to increase stemness and favor mammary tumorigenesis in parous rats. Further research is required to delineate the mechanism by which parity alters the stemness characteristics of mammary stem cells reducing the risk of mammary cancers. Citation Format: Ramadevi Subramani, Adriana Estrada, Sheryl Rodriguez, Seeta Poudel, Jesse Foskey, Cynthia Jimenez, Kenneth Smith, Mark Shahinian, Abdallah Yazadi, Tugba Mehmetoglu-Gurbuz, Jackelyn Rocha, Rajkumar Lakshmanaswamy. Parity reduces the risk of mammary cancer by altering the characteristics of mammary stem cells [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-11-02.

Progesterone (P4) and estradiol (E2) have been shown to stimulate and regulate breast cancer proliferation via classical nuclear receptor signaling through progesterone receptor (PR) and estrogen receptor α (ERα), respectively. However, the basis of communication between PR/ERα and membrane receptors remains largely unknown. Here, we aim to identify classical and nonclassical endocrine signaling mechanisms that can alter cell proliferation through a possible crosstalk between PR, ERα, and progesterone receptor membrane component 1 (PGRMC1), a membrane receptor frequently observed in breast cancer cells. While P4 and E2 treatment increased cell proliferation of ER+/PR+/PGRMC1 overexpressing breast cancer cells, silencing ERα and PR or treatment with selective estrogen receptor modulator (SERM) tamoxifen, or (PR-antagonist) RU-486 decreased cell proliferation. All four treatments rapidly altered PGRMC1 mRNA levels and protein expression. Furthermore, P4 and E2 treatments rapidly activated EGFR a known interacting partner of PGRMC1 and its downstream signaling. Interestingly, downregulation of ERα by tamoxifen and ERα silencing decreased the expression levels of PGRMC1 with no repercussions to PR expression. Strikingly PGRMC1 silencing decreased ERα expression irrespective of PR. METABRIC and TCGA datasets further demonstrated that PGRMC1 expression was comparable to that of ERα in Luminal A and B breast cancers. Targeting of PR, ERα, and PGRMC1 confirmed that a crosstalk between classical and nonclassical signaling mechanisms exists in ER+ breast cancer cells that could enhance the growth of ER+/PR+/PGRMC1 overexpressing tumors.

Hepatitis C virus (HCV) infection is the prevalent risk factor for chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC) worldwide. The association between metabolic syndrome (MetS) and HCV infection has not been studied effectively, particularly among different ethnic/racial groups in the US. A retrospective cross-sectional study was conducted using data from the National Health and Nutrition Examination Survey (1999–2014). Unadjusted and adjusted associations were summarized using the prevalence ratio (PR) and 95% confidence interval (CI) after exploring possible interactions. In the overall population, MetS was significantly associated with HCV infection with an interaction of age. After adjusting for all potential confounders, MetS was found to be significantly associated with HCV among non-obese and younger adults of age less than 60 years (PR 1.67, 95% CI 1.21–2.30, p = 0.002). MetS was also associated with an increased prevalence of HCV in each racial/ethnic group, while the association was strongly modified by age and obesity status of the subjects in different ethnic/racial groups. MetS or its components are associated with an increased prevalence of HCV in some sub-populations of all ethnic/racial groups in the US. A better understanding of the pathophysiology of MetS associated with HCV is important as MetS may have a role in HCV infection treatment outcomes.

Introduction: Early pregnancy has been shown to decrease the life-time risk of mammary cancer. Further, systemic alterations in circulating levels of growth hormone (GH) and prolactin (PRL) have been associated with the decreased risk. GH and PRL have been shown to affect the mammary stroma and epithelium. Carcinogenesis is a multistep process and there are several ways in which the host environment can affect progression of initiated cells to neoplasia. During normal and tumor development complex interactions occur between epithelial cells and stromal cells in the tissue microenvironment. These epithelial-stromal interactions in the microenvironment play a crucial role in the progression of mammary tumors. Determining the epithelial-stromal regulation by GH and PRL in the mammary gland of early parous rats is expected to improve our understanding of the dynamics of the epithelium and stromal interactions in mammary carcinogenesis. Materials and Methods: The inguinal mammary fat pad was cleared of the host mammary gland in 3-4-week-old female Lewis rats. One group (n=20) of rats were exposed to MNU at 7 weeks of age, and another group (n=20) of rats were not exposed to MNU. A subset (n=10) of rats from each of these experimental groups were mated at 9 weeks and allowed to go through a full-term pregnancy. The mothers were allowed to lactate for 3 weeks and weaned. All animals were terminated 6 weeks post-weaning. Mammary epithelial cells (MECs) were isolated using a standard collagenase cell dissociation procedure. The isolated MECs (5 × 105) were transplanted into the gland-free fat pads of respective hosts (n=30). MECs isolated from control and carcinogen treated age-matched nulliparous (AMNP) rats were transplanted into the gland-free fat pads of parous hosts and similarly MECs from control and carcinogen treated parous were transplanted into gland-free fats pads of AMNP hosts. In brief, we studied the following groups to understand the influence of early parity on epithelial-stromal interactions involved in mammary carcinogenesis: 1) carcinogen treated MECs from AMNP rats was transplanted into untreated parous rats; 2) carcinogen treated MECs from parous rats was transplanted into untreated AMNP rats; 3) untreated MECs from AMNP rats was transplanted into carcinogen treated parous rats and 4) untreated MECs from parous rats was transplanted into carcinogen treated AMNP rats. In another experiment, we treated a subset of the above mentioned groups with GH or PRL (n=10). Mammary carcinogenesis was monitored weekly for incidence, multiplicity, and latency. The cancerous nature of the palpable tumors was confirmed by histopathological analysis. Results: Our results demonstrate that when MECs from AMNP rats were transplanted to parous hosts they did not grow further to make palpable cancers. In contrast when MECs from parous rats were transplanted to AMNP they formed palpable cancers. Further, administration of GH or PRL increased carcinogenesis in parous rats. Conclusion: These findings indicate that the epithelial stromal interactions are important for mammary carcinogenesis and they are influenced significantly by GH and PRL. Citation Format: Ramadevi Subramani, Adriana Galvez, Diego Pedroza, Alejandro Bencomo, Madeline Dixon, Rajkumar Lakshmanaswamy. Growth hormone and prolactin influences mammary epithelial and stromal interactions in early parity induced protection against breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-12-02.

BackgroundThe higher level of background parenchymal enhancement (BPE) at breast MRI has the potential for early detection and prediction of the risk of breast cancer. However, conflicting findings have been reported about the association between the level of BPE at breast MRI and the presence of breast cancer.PurposeTo evaluate the association between qualitative and quantitative BPE at dynamic contrast material-enhanced MRI and breast cancer among populations with average risk and high risk separately.Materials and MethodsA retrospective meta-analysis of observational studies comparing either qualitative or quantitative assessments of BPE in women with and women without breast cancer was performed for studies published through July 2018. Pooled odds ratios (ORs) or standardized mean differences and 95% confidence intervals (CIs) were estimated by using DerSimonian-Laird random-effects models. The heterogeneity across the studies was measured by using the statistic

Growth hormone receptor (GHR) plays a vital role in breast cancer chemoresistance and metastasis but the mechanism is not fully understood. We determined if GHR could be a potential therapeutic target for estrogen receptor negative (ER−ve) breast cancer, which are highly chemoresistant and metastatic. GHR was stably knocked down in ER-ve breast cancer cells and its effect on cell proliferation, metastatic behavior, and chemosensitivity to docetaxel (DT) was assessed. Microarray analysis was performed to identify potential GHR downstream targets involved in chemoresistance. GHR and ATP-binding cassette sub-family G member 2 (ABCG2) overexpression and knockdown studies were performed to investigate the mechanism of GHR-induced chemoresistance. Patient-derived xenografts was used to study the effect of GHR and ABCG2. Immunohistochemical data was used to determine the correlation between GHR, pAKT, pmTOR, and ABCG2 expressions. GHR silencing drastically reduced the chemoresistant and metastatic behavior of ER-ve breast cancer cells and also inhibited AKT/mTOR pathway. In contrast, activation, or overexpression of GHR increased chemoresistance and metastasis by increasing the expression and promoter activity, of ABCG2. Inhibition of JAK2/STAT5 signaling repressed GHR-induced ABCG2 promoter activity and expression. Further, ABCG2 knockdown significantly increased the chemosensitivity. Finally, patient-derived xenograft studies revealed the role of GHR in chemoresistance. Overall, these findings demonstrate that targeting GHR could be a novel therapeutic approach to overcome chemoresistance and associated metastasis in aggressive ER-ve breast cancers., Breast cancer: A protein to target for double effect A new way to treat some forms of breast cancer might be achieved by drugs that interact with a cell surface protein that binds to growth hormone and transmits growth-inducing signals into the cells. Rajkumar Lakshmanaswamy and colleagues at Texas Tech University, El Paso, USA, investigated the role of growth hormone receptor (GHR) protein in human breast cancer cells. Silencing the gene for GHR dramatically reduced the ability of the cells to multiply and spread, and also reduced the cells’ resistance to anti-cancer drugs. Increasing the activity of the GHR gene increased the cells’ cancerous activity and their resistance to chemotherapy. The research identified some molecular signaling pathways inside cells that mediated these effects. Drugs interfering with GHR activity might inhibit the spread of cancer while making existing cancer cells more susceptible to treatment.

Simple Summary Breast cancer is one of the most frequently diagnosed cancers and it is the second leading cause of cancer-related death in women. Early first full-term pregnancy has been known to reduce the life-time risk of breast cancer. The actual mechanism by which pregnancy reduces the life-time risk of breast cancer is not well understood. It is well established that hormones are vital for a successful full-term pregnancy and they can also influence the risk of breast cancer. The emphasis has been placed mainly on the ovarian hormones estrogen and progesterone. It is also known that hypothalamic and pituitary hormones can impact the breast. In this study, we investigated how pregnancy alters the hypothalamic/pituitary hormones and what effect these hormonal alterations have on the risk of breast cancer development. Our results demonstrate that pregnancy persistently alters the hypothalamic–pituitary hormonal axis leading to the reduction of breast cancer risk. Abstract Early full-term pregnancy is known to reduce the lifetime risk of breast cancer. Although the phenomenon of parity-induced protection is well-established, the physiological mechanisms involved in this protection are not clear. Earlier reports have shown that pregnancy results in alterations of hormone levels. How pregnancy affects hypothalamic hormones and how the change, if any, influences breast cancer is not well understood. Seven-week-old female Lewis rats were given N-methyl-N-nitrosourea. Two weeks post carcinogen exposure, a set of females were housed with males to generate the parous rats and another set of rats served as the nulliparous controls. Mammary tumorigenesis was assessed for 9 months. Hypothalamic and pituitary levels of hormones were measured at various timepoints. Further, animals were also challenged with growth hormone and prolactin secretagogues to test the effect of pregnancy on the hypothalamic–pituitary hormonal axis. Persistent alterations in the level of growth hormone-releasing hormone, thyrotropin releasing hormone, dopamine, and somatostatin in the hypothalamus of parous animals was observed. Further, we also observed that pregnancy had a significant effect on the pituitary gland and its response to growth hormone and prolactin secretagogues. Our studies using the rodent model system demonstrate that pregnancy could be reducing the risk of breast cancer by persistently altering the hypothalamic–pituitary axis, which could have implications for breast cancers in humans as well.

The major challenge in chemotherapy lies in the gain of therapeutic resistance properties of cancer cells. The relatively small fraction of chemo-resistant cancer cells outgrows and are responsible for tumor relapse, with acquired invasiveness and stemness. We demonstrate that zinc-finger MYND type-8 (ZMYND8), a putative chromatin reader, suppresses stemness, drug resistance, and tumor-promoting genes, which are hallmarks of cancer. Reinstating ZMYND8 suppresses chemotherapeutic drug doxorubicin-induced tumorigenic potential (at a sublethal dose) and drug resistance, thereby resetting the transcriptional program of cells to the epithelial state. The ability of ZMYND8 to chemo-sensitize doxorubicin-treated metastatic breast cancer cells by downregulating tumor-associated genes was further confirmed by transcriptome analysis. Interestingly, we observed that ZMYND8 overexpression in doxorubicin-treated cells stimulated those involved in a good prognosis in breast cancer. Consistently, sensitizing the cancer cells with ZMYND8 followed by doxorubicin treatment led to tumor regression in vivo and revert back the phenotypes associated with drug resistance and stemness. Intriguingly, ZMYND8 modulates the bivalent or poised oncogenes through its association with KDM5C and EZH2, thereby chemo-sensitizing the cells to chemotherapy for better disease-free survival. Collectively, our findings indicate that poised chromatin is instrumental for the acquisition of chemo-resistance by cancer cells and propose ZMYND8 as a suitable epigenetic tool that can re-sensitize the chemo-refractory breast carcinoma.

Hepatocyte nuclear factor 1 homeobox alpha (HNF1α) is a transcription factor involved in endodermal organogenesis and pancreatic precursor cell differentiation and development. Earlier studies have reported a role for HNF1α in pancreatic ductal adenocarcinoma (PDAC) but it is controversial. The mechanism by which it impacts PDAC is yet to be explored in depth. In this study, using the online databases we observed that HNF1α is upregulated in PDAC, which was also confirmed by our immunohistochemical analysis of PDAC tissue microarray. Silencing HNF1α reduced the proliferative, migratory, invasive and colony forming capabilities of pancreatic cancer cells. Key markers involved in these processes (pPI3K, pAKT, pERK, Bcl2, Zeb, Snail, Slug) were significantly changed in response to alterations in HNF1α expression. On the other hand, overexpression of HNF1α did not induce any significant change in the aggressiveness of pancreatic cancer cells. Our results demonstrate that reduced expression of HNF1α leads to inhibition of pancreatic cancer growth and progression, which indicates that it could be a potential oncogene and target for PDAC.

Introduction : Hispanic women residing along the US-Mexico border have the highest cervical cancer incidence rates in the US. Genital human papillomavirus (HPV) is the major causative agent, but more information is needed about the prevalence and distribution of genital HPV subtypes in this high-risk population. Methods : A population-based cross-sectional study of uninsured Hispanic women along the US-Mexico border was conducted and participants had their cervical specimens undergo DNA extraction followed by HPV genotype testing using the Linear Assay from Roche® Diagnostics, to identify 37 genital HPV subtypes. Results : Among the 585 women aged 21-65 years, 584 self-identfied as Hispanic. Any HPV subtype prevalence was 53.2% (95% CI: 49.0%-57.3%) and of these 52% (i.e. 27.5% of the total) had single infections and 48% (i.e. 25.6% of the total) had multiple infections. High-risk HPV prevalence was 15.6% (95% CI: 24-31.3%). The mean number of subtypes among those testing positive was 2.1 (SD 1.6). The prevalence of any HPV and high-risk HPV showed a U shaped pattern with age; and prevalence of 16/18 and non-16/18 high-risk subtypes (e.g. 31, 33, 35, 39, 45, 51, 52, 58); also varied with age. Forty-one percent of high-risk HPV occurrences were of a subtype not covered by the current nonavalent HPV vaccine. Discussion : Our findings suggest a different high-risk HPV subtype pattern and age distribution among Hispanic women in the USA, which could have implications for future cervical cancer prevention strategies.

Much emphasis is placed on estrogen (E2) and estrogen receptor (ER) signaling as most research is focused on understanding E2 and ER’s ability to enhance proliferative signals in breast cancers. Progesterone (P4) is important for normal mammary gland development, function and menstrual control. However, P4 and its receptors (PRs) in breast cancer etiology continue to be understudied and its role in breast cancer remains controversial. The Women’s Health Initiative (WHI) clinical trial clearly demonstrated the importance of progestogens in breast cancer development. P4 has historically been associated with classical-signaling through nuclear receptors, however non-classical P4 signaling via membrane receptors has been described. Progestogens have the ability to bind to nuclear and membrane receptors and studies have demonstrated that both can promote breast cancer cell proliferation and breast tumor growth. In this review, we attempt to understand the classical and non-classical signaling role of P4 in breast cancers because both nuclear and membrane receptors could become viable therapeutic options for breast cancer patients.

Hypoxanthine phosphoribosyl transferase 1 (HPRT1) is traditionally believed to be a housekeeping gene, however, recent reports suggest that it is upregulated in several cancers and is associated with clinical outcomes. HPRT1 is located on chromosome X and encodes the HPRT enzyme, which functions in recycling nucleotides to supply for DNA and RNA synthesis in actively dividing cells. Here, we used transcriptomic analyses to interrogate its expression across all known cancer types and elucidated its role in regulating gene expression in breast cancer. We observed elevated HPRT1 RNA levels in malignant tissues when compared to normal controls, indicating its potential as a diagnostic and prognostic marker. Further, in breast cancer, the subtype-specific analysis showed that its expression was highest in basal and triple-negative breast cancer, and HPRT1 knockdown in breast cancer cells suggested that HPRT1 positively regulates genes related to cancer pathways. Collectively, our results essentially highlight the importance of and change the way in which HPRT1&rsquo, s function is studied in biology, warranting careful examination of its role in cancer.

Long noncoding RNAs (lncRNAs) have recently gained considerable attention as key players in biological regulation; however, the mechanisms by which lncRNAs govern various disease processes remain mysterious and are just beginning to be understood. The ease of next-generation sequencing technologies has led to an explosion of genomic information, especially for the lncRNA class of noncoding RNAs. LncRNAs exhibit the characteristics of mRNAs, such as polyadenylation, 5' methyl capping, RNA polymerase II-dependent transcription, and splicing. These transcripts comprise more than 200 nucleotides (nt) and are not translated into proteins. Directed interrogation of annotated lncRNAs from RNA-Seq datasets has revealed dramatic differences in their expression, largely driven by alterations in transcription, the cell cycle, and RNA metabolism. The fact that lncRNAs are expressed cell- and tissue-specifically makes them excellent biomarkers for ongoing biological events. Notably, lncRNAs are differentially expressed in several cancers and show a distinct association with clinical outcomes. Novel methods and strategies are being developed to study lncRNA function and will provide researchers with the tools and opportunities to develop lncRNA-based therapeutics for cancer.

Autophagy is a complex process that plays a central role in maintaining cellular homeostasis by breaking down macromolecules and utilizing the metabolites as energy. This allows cells to maintain efficient ATP levels and promote cell survival by recycling macromolecules or dysfunctional organelles. Macromolecule degradation takes place in the lysosome and is identified as macroautophagy, microautophagy, or chaperone-mediated autophagy. Autophagy is also activated in response to cellular nutrient starvation as low glucose levels will cause cells to break down amino acids, such as glutamine. Glutaminolysis is able to support the tricarboxylic acid (TCA) cycle and when cells undergo severe starvation they can produce adequate ATP and NADPH levels. The underlying mechanism of autophagy is regulated by specific genes, primarily known as autophagy-related genes (ATGs). Although autophagy is critical for normal cell maintenance, cancer cells utilize autophagy to eliminate the demanding metabolic stress that is put on the cells allowing them to continue to grow and divide. Cancers with elevated autophagy activity are able to regulate important proliferative signaling pathways, including the PI3K/AKT/mTOR. Mutations in tumor suppressor genes, KRAS, Tp53, BRCA2, and PTEN have demonstrated the ability to activate autophagy, allowing for further uncontrolled growth of cancers. Autophagy has dual effects; normal cells can utilize it to promote autophagic cell death under stressful conditions, while cancer cells use it to induce chemo-resistance, promote cellular growth and division even under stressful metabolic conditions. Patients that present with elevated genes associated with autophagy could benefit from pharmacological inhibition of autophagy and targeted therapies to those genes. Here, we complied the role of autophagy regulation in cancer and cancer cell metabolism.

Long noncoding RNAs (lncRNAs) have recently gained considerable attention as key players in biological regulation; however, the mechanisms by which lncRNAs govern various disease processes remain mysterious and are just beginning to be understood. The ease of next-generation sequencing technologies has led to an explosion of genomic information, especially for the lncRNA class of noncoding RNAs. LncRNAs exhibit the characteristics of mRNAs, such as polyadenylation, 5' methyl capping, RNA polymerase II-dependent transcription, and splicing. These transcripts comprise more than 200 nucleotides (nt) and are not translated into proteins. Directed interrogation of annotated lncRNAs from RNA-Seq datasets has revealed dramatic differences in their expression, largely driven by alterations in transcription, the cell cycle, and RNA metabolism. The fact that lncRNAs are expressed cell- and tissue-specifically makes them excellent biomarkers for ongoing biological events. Notably, lncRNAs are differentially expressed in several cancers and show a distinct association with clinical outcomes. Novel methods and strategies are being developed to study lncRNA function and will provide researchers with the tools and opportunities to develop lncRNA-based therapeutics for cancer.

Breast cancer is one of the most common cancers diagnosed in women. Approximately two-thirds of all breast cancers diagnosed are classified as hormone dependent, which indicates that hormones are the key factors that drive the growth of these breast cancers. Ovarian and pituitary hormones play a major role in the growth and development of normal mammary glands and breast cancer. In particular, the effect of the ovarian hormone estrogen has received much attention in regard to breast cancer. Pituitary hormones prolactin and growth hormone have also been associated with breast cancer. Although the role of these pituitary hormones in breast cancers has been studied, it has not been investigated extensively. In this review, we attempt to compile basic information from most of the currently available literature to understand and demonstrate the significance of growth hormone in breast cancer. Based on the available literature, it is clear that growth hormone plays a significant role in the development, progression, and metastasis of breast cancer by influencing tumor angiogenesis, stemness, and chemoresistance.

Early parity reduces the risk of breast cancer in women while nulliparity and late parity increase the risk of breast cancer. In order to translate this protection to women where early pregnancy is not feasible, much work has focused on understanding how parity confers protection against breast cancer, the molecular mechanisms by which this occurs is still not well understood. Healthy parous and nulliparous women were recruited for this study. We assessed serum protein profiles of early parous, late parous, and nulliparous women using the Phospho Explorer antibody array. Significantly altered proteins identified were validated by Western blot analysis. In silico analysis was performed with the data obtained. Our findings indicate increased phosphorylation levels of CDK1, AKT1 and Epo-R increased cell cycle and cell proliferation in late/nulliparous women. Increased levels of LIMK1, paxillin, caveolin-1, and tyrosine hydroxylase in late/nulliparous women demonstrate enhanced cell stress while decreased activity of p-p53 and pRAD51 in late/nulliparous women indicates decreased apoptosis and increased genomic instability. Further, increased levels of pFAK, pCD3zeta, pSTAT5B, MAP3K8 in early parous women favor enhanced innate/adaptive immunity. Overall, we have identified a unique protein signature that is responsible for the decreased risk of breast cancer and these proteins can also serve as biomarkers to predict the risk of breast cancer.

// Ramadevi Subramani 1 , Elizabeth Gonzalez 2 , Sushmita Bose Nandy 1 , Arunkumar Arumugam 1 , Fernando Camacho 2 , Joshua Medel 2 , Damilola Alabi 2 , Rajkumar Lakshmanaswamy 1, 2 1 Center of Emphasis in Cancer Research, Department of Biomedical Sciences, Texas Tech University Health Sciences Center, Paul L. Foster School of Medicine, El Paso, Texas-79905, USA 2 Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, El Paso, Texas-79905, USA Correspondence to: Rajkumar Lakshmanaswamy, email: rajkumar.lakshmanaswamy@ttuhsc.edu Keywords: pancreatic cancer, gedunin, metastasis, hedgehog/gli signaling, apoptosis Received: December 21, 2015 Accepted: February 25, 2016 Published: March 14, 2016 ABSTRACT INTRODUCTION: The lack of efficient treatment options for pancreatic cancer highlights the critical need for the development of novel and effective chemotherapeutic agents. The medicinal properties found in plants have been used to treat many different illnesses including cancers. This study focuses on the anticancer effects of gedunin, a natural compound isolated from Azadirachta indica . METHODS: Anti–proliferative effect of gedunin on pancreatic cancer cells was assessed using MTS assay. We used matrigel invasion assay, scratch assay, and soft agar colony formation assay to measure the anti–metastatic potential of gedunin. Immunoblotting was performed to analyze the effect of gedunin on the expression of key proteins involved in pancreatic cancer growth and metastasis. Gedunin induced apoptosis was measured using flow cytometric analysis. To further validate, xenograft studies with HPAC cells were performed. RESULTS: Gedunin treatment is highly effective in inducing death of pancreatic cancer cells via intrinsic and extrinsic mediated apoptosis. Our data further indicates that gedunin inhibited metastasis of pancreatic cancer cells by decreasing their EMT, invasive, migratory and colony formation capabilities. Gedunin treatment also inhibited sonic hedgehog signaling pathways. Further, experiments with recombinant sonic hedgehog protein and Gli inhibitor (Gant-61) demonstrated that gedunin induces its anti–metastatic effect through inhibition of sonic hedgehog signaling. The anti–cancer effect of gedunin was further validated using xenograft mouse model. CONCLUSION: Overall, our data suggests that gedunin could serve as a potent anticancer agent against pancreatic cancers.

IGF-1R signaling controls various vital cellular functions and this signaling is deregulated in many cancers, including pancreatic cancer. Several efforts have mainly focused on inhibiting the IGF-1R signaling cascade. The outcomes of these focused preclinical studies have been positive, whereas clinical trials of IGF-1R inhibitors in pancreatic cancer have failed, raising the questions about this therapeutic approach. This necessitates a better understanding of the role of IGF-1R signaling in pancreatic cancer. We investigated the impact of IGF-1R signaling on crucial transcription factors and identified the FOXC1 as one of the crucial regulator of IGF-1R signaling. We employed genetic approaches to overexpress and silence FOXC1 in pancreatic cancer cells. Our results demonstrate that IGF-1R and FOXC1 seem to positively regulate each other. Further, FOXC1 increased the metastatic abilities of pancreatic cancer cells by enhancing cell proliferation, migration, invasion, epithelial-to-mesenchymal transition, and angiogenesis. The data from xenograft experiments further established the importance of FOXC1 in pancreatic tumorigenesis. In conclusion, FOXC1 is a potent oncogenic transcription factor, which promotes pancreatic cancer growth and metastasis. Thus, targeting FOXC1 could be a potential therapeutic strategy against pancreatic cancer.

Complementary and alternative medicine (CAM) has been in use among cancer patients for a long time. There are several types of CAM that are practiced in various parts of the world. For example, traditional medicinal practices followed in India and China are frequently used by cancer patients. CAM is broadly classified into five different categories: (1) traditional medicines, (2) mind-body interventions, (3) biology-based practices, (4) manipulative body-based practices, and (5) energy medicine. In this review, we have compiled data from the available literature regarding CAM use in breast cancer patients. We have highlighted the current concepts and the need for more structured studies to facilitate the implementation of CAM as a mainstream option for cancer patients.

Decades of cancer research have led to substantial progress in the treatment of primary breast cancers. Despite of the advancement in this field, treating a metastatic disease has remained a mammoth task. One of the possible theories explaining metastatic disease involves the cancer stem cells (CSCs). CSCs have been shown to be an integral part of solid tumors. The process of metastasis involves the fine orchestration between CSCs and other microenvironmental factors. This chapter will provide an overview about the process of metastasis and the interactive role of CSCs with the components of the microenvironment in each phase of the metastatic cascade.