The molecular mechanisms underlying the progression of breast cancer to more malignant behavior are not completely understood at the present time and are believed to involve deregulation of cross-talk between estrogen receptor and growth factor signaling, and also ligand-independent ER transactivation. For example, activation of p21-activated kinase (Pak1), a major target of growth factor signaling, regulates cell motility, invasiveness and survival, all of which are required for both tumor development and also normal mammary gland development. Despite the remarkable growth of information about growth factors and Pak1 biology, the mechanism by which novel Pak1 targets regulate these processes in breast cancer remains elusive. Our preliminary studies have discovered for the first time that ER is a physiological target of Pak1 and that the functional outcome of ER-Pak1 pathway may be closely influenced by the phosphorylation status of NRIF3 and Ese1, two novel ER-interacting Pak1 substrates with opposing functions. This proposal represents a continuing effort of the PI to investigate the mechanism by which critical physiologic Pak1 substrates modulate ER transactivation and participates in the development of tumorigenic phenotypes in breast cancer cells. Our working hypothesis is that """"""""deregulation of Pak1 activity stimulates the ER pathway, and consequently, contributes to an enhanced hormone response, hormone-independence, and tumorigenesis of breast tumor cells; these phenotypic effects of ER might be controlled by the modulation of actions of NRIF3 and Ese1, two novel ER-interacting Pak1 substrates that modulate the ER transactivation in a stimulatory or inhibitory manner, respectively."""""""" This proposal will clarify the role of growth factor signaling in hormone-independence and breast cancer progression by defining the mechanistic significance of specific downstream physiologic targets of Pak1 such as ER, NRIF3 and Ese1, and to establish the role of ER-Ser305 and Ser118 activation in the normal mammary gland development and tumorigenesis. To address these hypotheses, our Specific Aims are to determine: (1 )The functional significance of Pak1-ER pathway in the mammary gland development and tumorigenesis; (2) The influence of Pak1 regulation of NRIF3-Ser28 in the action of ER and associated phenotypic changes; (3) The role of Ese1 and its phosphorylation by Pak1 in modifying ER functions and breast cancer biology; (4)The expression characteristics and significance of Pak1, ER, and Ese1 during multi-step pathogenesis of breast carcinoma and in-patients with invasive breast cancer. An innovative aspect of our proposal is the use of novel in vitro, in vivo and transgenic models, as well as human breast tumors with follow-up data to gain new insights about the mechanistic and functional significance of Pak1-ER pathway by NRIF3 and Ese1 in breast cancer cells. These studies will uniquely define the mechanisms through which ER and its upstream Pak1 kinase and downstream coregulators NRIF3 and Ese1 modulate hormone action. This research is significant in that the knowledge gained from this research will enhance our understanding of the critical regulatory pathways with established roles in breast cancer progression.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA090970-06
Application #
7101009
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Snyderwine, Elizabeth G
Project Start
2001-05-18
Project End
2010-04-30
Budget Start
2006-05-01
Budget End
2007-04-30
Support Year
6
Fiscal Year
2006
Total Cost
$252,120
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Microbiology/Immun/Virology
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Kumar, Rakesh; Sanawar, Rahul; Li, Xiaodong et al. (2017) Structure, biochemistry, and biology of PAK kinases. Gene 605:20-31
AlHossiny, Midrar; Luo, Linlin; Frazier, William R et al. (2016) Ly6E/K Signaling to TGF? Promotes Breast Cancer Progression, Immune Escape, and Drug Resistance. Cancer Res 76:3376-86
Kumar, Rakesh; Wang, Rui-An (2016) Structure, expression and functions of MTA genes. Gene 582:112-21
Kumar, R; Li, D-Q (2016) PAKs in Human Cancer Progression: From Inception to Cancer Therapeutic to Future Oncobiology. Adv Cancer Res 130:137-209
Ohshiro, Kazufumi; Kumar, Rakesh (2015) MTA1 regulation of ER? pathway in salivary gland carcinoma cells. Biochem Biophys Res Commun 464:1016-1021
Motwani, Mona; Li, Da-Qiang; Horvath, Anelia et al. (2013) Identification of novel gene targets and functions of p21-activated kinase 1 during DNA damage by gene expression profiling. PLoS One 8:e66585
Pakala, Suresh B; Nair, Vasudha S; Reddy, Sirigiri DivijendraNatha et al. (2012) Signaling-dependent phosphorylation of mitotic centromere-associated kinesin regulates microtubule depolymerization and its centrosomal localization. J Biol Chem 287:40560-9
Sánchez-Solana, Beatriz; Motwani, Mona; Li, Da-Qiang et al. (2012) p21-activated kinase-1 signaling regulates transcription of tissue factor and tissue factor pathway inhibitor. J Biol Chem 287:39291-302
Li, Da-Qiang; Nair, Sujit S; Ohshiro, Kazufumi et al. (2012) MORC2 signaling integrates phosphorylation-dependent, ATPase-coupled chromatin remodeling during the DNA damage response. Cell Rep 2:1657-69
Ohshiro, Kazufumi; Bui-Nguyen, Tri M; Divijendra Natha, Reddy S et al. (2012) Thrombin stimulation of inflammatory breast cancer cells leads to aggressiveness via the EGFR-PAR1-Pak1 pathway. Int J Biol Markers 27:e305-13

Showing the most recent 10 out of 70 publications