Classical and Non-Classical Progesterone Signaling in Breast Cancers

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.</jats:p

Abstract 1668: Induction of Autophagy by a novel agent promotes the growth arrest in breast cancer cells.

Abstract Breast cancer is a highly complex disease due to its heterogeneity in nature; that often impedes the current therapeutic options. Autophagy is a catabolic process which plays a vital role in both progressions as well as in the treatment of cancer. In fact, the role of autophagy in cancer is still unclear. Our lab is focusing on small molecules, which may induce autophagy that may result in growth arrest in breast cancer cells. In our preliminary screening studies, we have identified a small molecule, Nimocinol Acetate (NA) which induces autophagy that resulted in inhibition of growth of estrogen-positive (MCF-7) and estrogen-negative (MDA-MB-231) breast cancer cells. Molecular analysis showed the significant induction of LC-3B and ATG-3 in NA treated cells as compared to other autophagy-regulators like Atg5, Atg7, Atg12, and beclin-1, which convey the importance of ATG3 and LC3B markers in induction of autophagy. The immunofluorescence analysis confirmed the formation of acidic autophagic vesicles upon NA treatment. To further ascertain the involvement of lysosomes and autophagosomes, we specifically blocked ATG-3 and LC-3B expression by siRNA and then subjected to immunofluorescence assay. The observed results confirmed the contribution and activation of these two molecules is required for the induction of autophagy. Interestingly, no significant changes were obseverved either in the cell cycle regulation or in induction of apoptosis, which revealed that the activation of autophagy may be responsible for NA mediated growth inhibition in breast cancer cells. Currently, we are planning to conduct xenograft studies, which may suggest the in vivo efficacy and pharmacokinetic potential of NA. The present study concludes that NA could be a potential agent either alone or in combination with other chemotherapeutic agents with a novel strategy to combat breast cancer. Citation Format: Ramadevi Subramani Reddy, Pallab Pahari, Chendil Damodaran. Induction of Autophagy by a novel agent promotes the growth arrest in breast cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1668. doi:10.1158/1538-7445.AM2013-1668</jats:p

miRNome and Functional Network Analysis of PGRMC1 Regulated miRNA Target Genes Identify Pathways and Biological Functions Associated With Triple Negative Breast Cancer.

Background: Increased expression of the progesterone receptor membrane component 1, a heme and progesterone binding protein, is frequently found in triple negative breast cancer tissue. The basis for the expression of PGRMC1 and its regulation on cellular signaling mechanisms remain largely unknown. Therefore, we aim to study microRNAs that target selective genes and mechanisms that are regulated by PGRMC1 in TNBCs. Methods: To identify altered miRNAs, whole human miRNome profiling was performed following AG-205 treatment and PGRMC1 silencing. Network analysis identified miRNA target genes while KEGG, REACTOME and Gene ontology were used to explore altered signaling pathways, biological processes, and molecular functions. Results: KEGG term pathway analysis revealed that upregulated miRNAs target specific genes that are involved in signaling pathways that play a major role in carcinogenesis. While multiple downregulated miRNAs are known oncogenes and have been previously demonstrated to be overexpressed in a variety of cancers. Overlapping miRNA target genes associated with KEGG term pathways were identified and overexpression/amplification of these genes was observed in invasive breast carcinoma tissue from TCGA. Further, the top two genes ( Conclusions: Thus, our data demonstrates that therapeutic targeting of PGRMC1 in aggressive breast cancers leads to the activation of miRNAs that target overexpressed genes and deactivation of miRNAs that have oncogenic potential

C-Reactive Protein - A Promising Marker for Patients with Ischemic Heart Disease along with Covid-19 among South Indian Population

BACKGROUND New corona virus respiratory syndrome is a health emergency due to high infectivity and high case fatality in patients with comorbid conditions like ischemic heart disease. The diagnostic methods of corona virus disease (Covid-19) are still in experimental stage. Hence, a sensitive and specific disease progression marker of Covid-19 is needed. CRP (C-reactive protein) is synthesised by liver. It is elevated in infection and inflammatory conditions as it is an acute phase protein. The purpose of this study was to evaluate CRP as a promising marker for predicting severity of Covid-19 in ischemic heart disease patients and to correlate the impact of CRP with other circulating cardiac biomarkers in different age groups and both sexes. METHODS This is a cross sectional study done among south Indian population mostly from Tamil Nadu and Andhra Pradesh. 232 cases were selected and divided into two groups based on age, sex and confirmed Covid-19 positive cases by RT-PCR (Reverse transcription-polymerase chain reaction), admitted and treated in Rajiv Gandhi Government General Hospital, Chennai. RESULTS In this study, CRP levels were elevated in the age group of 50 - 70 years (66.96 ± 70.09 mg/dL) than CRP levels of age group 30 - 50 years (82.31 ± 90.23 mg/dL) and P value was found to be significant in the age group of 50 - 70 years. Lactate dehydrogenase (LDH) levels were elevated in the age group of 30 - 50 years (380.77 ± 252.23 U/L) than the LDH levels of age group 50 - 70 years (393.53 ± 206.83 U/L) and P value was found to be significant in the age group of 30 - 50 years. Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and creatine kinase (CK) levels are the additional cardiac enzymes found to be elevated in this study. CRP showed a positive correlation with LDH (r = 0.221 P &lt; 0.001) in both males (r = 0.06 and P &lt; 0.001) and females (r = 0.45 and P &lt; 0.001) with a significant P value. Receiver operating characteristics (ROC) curves for CRP Vs age group shows a sensitivity of 91.15 % and specificity of 92.52 % and area under curve of 0.556. CONCLUSIONS CRP can be used as a promising marker for early detection and timely intervention of ischemic heart disease in Covid-19 patients especially in the age group of 50 - 70 years and thereby reduces the mortality. KEYWORDS Biomarkers, Heart Disease, Mortality, Prognosis</jats:p

Abstract 4673: Parity and short-term estradiol treatment confers protection against breast cancer by suppressing cell survival and migration

Abstract Early pregnancy is the only natural phenomenon known to confer protection against breast cancer. We have earlier demonstrated that short-term treatment with pregnancy levels of estradiol (STET) is very effective in preventing mammary carcinogenesis. The underlying mechanisms behind the protective effect of parity and STET remain unclear. In the current study, we attempted to delineate the influence of the mammary gland microenvironment on mammary carcinogenesis among parous and STET compared to age matched virgin rats. Parous, STET, and virgin (control) Sprague Dawley rats were administered N-methyl-N-nitrosourea (50mg/kg BW) at 15 weeks of age. Mammary cancer development was monitored by weekly palpations for 9 months post carcinogen treatment. A subset of rats (n = 4) were euthanized five weeks post carcinogen treatment. Mammary gland samples were surgically excised and used for histological and molecular analysis. Our analysis demonstrated that parity and STET resulted in reduced expression of cell survival markers (pAKT, pmTOR), extracellular matrix mediated signaling proteins (ERK1/2, pFAK, Itgb1) hormonal (ER, PR, GHR) and growth factor receptors (pEGFR, pIGFR1) compared to age matched virgin group. Further, expression of EMT markers and regulators of cell migration were significantly reduced in parous and STET mammary glands. MicroRNA analysis disclosed that both parity and STET differentially regulated the expression of 23 microRNAs. Among these 18 microRNAs were down regulated and 5 microRNAs were up regulated in both parous and STET treatment. In silico analysis revealed that several of the differentially regulated microRNAs are direct regulators of the cell survival and cell migratory proteins. Parity and STET by altering microRNA expression influences cell survival, cell migration and cell death signaling pathways reduces the cancer promoting microenvironment in the mammary gland. Citation Format: Arunkumar Arumugam, Ramadevi Subramani, Sushmita Nandy, Duy Do, Rajkumar Lakshmanaswamy. Parity and short-term estradiol treatment confers protection against breast cancer by suppressing cell survival and migration. [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 4673. doi:10.1158/1538-7445.AM2015-4673</jats:p