Estrogen receptor positive (ER+) breast tumors are the most commonly diagnosed tumors of the breast and account for more breast cancer deaths than all other types combined. When detected in its early stages, ER+ breast cancer is well managed with hormone therapies that block the activity of the receptor or the biosynthesis of estrogens; however, patients with advanced disease and those who relapse during hormone therapy remain incurable. The role of estrogen (17-estradiol, E2), in ER+ tumor progression is paradoxical. E2 induces tumor growth by activating ER; however, clinical data show that invasive ER+ breast tumors are more common in women post menopause, i.e. after E2 levels have declined. Importantly, several early studies suggest that ER activity has a protective role against invasion and metastasis. Therefore, there is a need to understand ER regulation of invasion apart from its known role in regulating tumor growth. Actin remodeling plays a central role in the regulation of invasion; however, hormone regulation of actin remodeling is not well understood. Recently, we identified a novel actin cytoskeletal remodeling process that suppresses cancer cell invasion by increasing cortical actomyosin bundles. These Suppressive Cortical Actin Bundles (herein denoted by SCABs, for simplicity) impede membrane protrusions, which are crucial for invasive activity. This actin remodeling process that generates SCABs is mediated by the actin binding protein Profilin-2, the actin-polymerization factor, EVL, and activated Myosin (P2EM-actin). Suppression of P2EM-actin decreases SCABs, thus lifting the brakes on protrusive activity and promoting invasion. In our preliminary studies, we found that protrusion is dependent on another actin remodeling process mediated by Profilin-1, Rac GTPase and Arp2/3 (P1RA-actin), which is antagonized by P2EM-actin. Moreover, our most recent data demonstrate that ER promotes the transcription of EVL, the driver of polymerization in P2EM-actin. Based on these findings, we hypothesize that ER activity suppresses invasion by promoting P2EM-actin, thus increasing SCABs and suppressing P1RA-actin mediated protrusions. We will test our hypothesis by pursuing the following specific aims (SAs). SA1 is to determine the actin remodeling caused by altering ER activity and the mechanism by which it modulates protrusion and invasion. We hypothesize that ER inhibits invasion by promoting EVL transcription, thus enhancing P2EM-actin, increasing the generation of SCABs and suppressing protrusion. SA2 is to identify the effects of altering ER activity on the antagonism between P2EM-actin and P1RA-actin and the consequent effects on invasive behavior. We hypothesize that ER suppression promotes invasion by decreasing P2EM-actin thus enhancing P1RA-actin mediated protrusions. If successful, our proposed studies will have a significant impact by establishing a novel mechanism by which ER prevents invasion, and by laying the groundwork for future clinical studies focused on treatment modalities that would particularly benefit patient afflicted with ER+ tumors.

Public Health Relevance

The studies presented here investigate the invasive behavior of estrogen receptor positive (ER+) breast cancer. Particularly, they are focused on identifying a novel mechanism by which ER activity suppresses invasion of ER+ breast cancer cells. The results from these studies will shed some light on the protective effects of estrogen against metastatic progression of ER positive breast tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA196885-03
Application #
9302320
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Sathyamoorthy, Neeraja
Project Start
2015-07-01
Project End
2020-06-30
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Arizona
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721
Padilla-Rodriguez, Marco; Parker, Sara S; Adams, Deanna G et al. (2018) The actin cytoskeletal architecture of estrogen receptor positive breast cancer cells suppresses invasion. Nat Commun 9:2980