Binoj C Nair    - research student -

Abstract: Estrogen receptor (ER) signaling plays an important role in breast cancer progression, and ER functions are influenced by coregulatory proteins. PELP1 (proline-, glutamic acid–, and leucine-rich protein 1) is a nuclear receptor coregulator that plays an important role in ER signaling. Its expression is deregulated in hormonal cancers. We identified PELP1 as a novel cyclin-dependent kinase (CDK) substrate. Using site-directed mutagenesis and in vitro kinase assays, we identified Ser477 and Ser991 of PELP1 as CDK phosphorylation sites. Using the PELP1 Ser991 phospho-specific antibody, we show that PELP1 is hyperphosphorylated during cell cycle progression. Model cells stably expressing the PELP1 mutant that lack CDK sites had defects in estradiol (E2)–mediated cell cycle progression and significantly affected PELP1-mediated oncogenic functions in vivo. Mechanistic studies showed that PELP1 modulates transcription factor E2F1 transactivation functions, that PELP1 is recruited to pRb/E2F target genes, and that PELP1 facilitates ER signaling cross talk with cell cycle machinery. We conclude that PELP1 is a novel substrate of interphase CDKs and that its phosphorylation is important for the proper function of PELP1 in modulating hormone-driven cell cycle progression and also for optimal E2F transactivation function. Because the expression of both PELP1 and CDKs is deregulated in breast tumors, CDK-PELP1 interactions will have implications in breast cancer progression. Cancer Res; 70(18); 7166–75. ©2010 AACR.

Abstract: Estrogen Receptor (ER) plays a central role in the development and progression of breast cancer. Hormonal therapy substantially improves disease-free survival of ER+ve breast tumors, however acquired resistance to endocrine therapies frequently occur. Emerging data implicate growth factor signaling pathways and their cross talk with ER as major cause of resistance. Both these pathways have been recently shown to use cell cycle machinery as downstream effectors in mediating therapy resistance. Several studies have demonstrated deregulation of cell cycle regulators and their cross talk with ER in therapy resistant tumors. The objective of this article is to review the underlying mechanisms by which tumor cells use cell cycle machinery to override hormonal therapy and to explore cell cycle machinery components as novel therapy targets for overcoming hormonal therapy resistance

Abstract: OBJECTIVE: To study alteration in karyometric variables to distinguish benign from malignant canine mammary tumors. STUDY DESIGN: Formalin-fixed, paraffin-embedded tissue sections from 16 cases of canine mammary tumors were stained with hematoxylin-eosin and analyzed for mean nuclear area, mean nuclear perimeter and shape factor. The morphometric descriptors were then correlated with conventional histologic diagnosis. RESULTS: On Mann-Whitney U-test, nuclear variables, that is, mean nuclear area and mean nuclear perimeter, revealed significant difference between malignant and benign groups (p < 0.01), while shape factor showed significant difference at p < 0.05. All morphometric descriptors showed significant correlation with each other and with histopathologic diagnosis. Contrary to expectations, shape factor was lower in benign compared to malignant tumors. In benign mammary tumors, the highest mean nuclear area and perimeter were 39.59 +/- 10.34 microm2 and 25.39 +/- 4.14 microm, respectively, for fibroadenoma; and in malignant tumors the highest mean nuclear area and perimeter were 48.44 +/- 12.89 microm2 and 27.36 +/- 4.31 microm, respectively, for papillary adenocarcinoma. CONCLUSION: This study provides insight into the alterations in karyometric variables in canine mammary tumors. Mean nuclear area and perimeter appear to have potential to differentiate benign and malignant canine mammary tumors.