ABSTRACT αvβ3 integrin-overexpression in tumor associated vasculature is a marker of poor prognosis in breast cancer. A positive correlation between αvβ3 integrin and overexpression of

Heregulin (HRG), a growth factor associated with breast cancer aggressiveness was recently demonstrated. Here, we addressed the role of αvβ3 in the proliferation and survival of

HRG-overexpressing breast cancer models. Expression of the RGD-binding integrins αvβ3, αvβ5 and αvβ6 was assessed in the HRG-overexpressing breast cancer cells MDA-MB-231, Hs578T (231/WT and

Hs578T/WT, respectively) and derived cells transfected with the antisense orientation of the HRG-β2 full-length cDNA (231/ASPOOL, 231/AS31 and Hs578T/AS15). Interestingly, only αvβ3

blockade of αvβ3 impaired HRG-promoted hyperactivation of ERK1/ERK2 MAPK without altering the activation of AKT. Flow cytometric analysis of the cell cycle demonstrated that αvβ3 antagonists

significantly decreased S- and G2/M-phase subpopulations of 231/WT and control 231/VEC cells. Comparable, this effect was linked to an increase in the levels and nuclear translocation of

the CDKs inhibitor p27Kip1. Besides downregulating αvβ3 and its driven signaling, HRG blockade led to decreased levels of CYR61 in 231/ASPOOL and 231/AS31 cells. Considering that CYR61 is

sufficient to upregulate the expression of αvβ3, we then assessed αvβ3 levels in MDA-MB-231 cell derivatives expressing the antisense orientation of the CYR61 cDNA (231/CYR61AS-5 and

231/CYR61AS-8). Remarkably, downregulation of CYR61 drastically decreased the levels of αvβ3 in the 231/CYR61-5 and 231/CYR61-8 cells, providing further evidence of a key role for CYR61 in

HRG-dependent αvβ3 overexpression. Moreover, blockade of CYR61 expression impaired the HRG-induced hyperactivation of ERK1/ERK2 MAPK without altering the activation status of AKT in

MDA-MB-231 cells, thus resembling the effects exerted by the downregulation of HRG expression as well as by functional blockade of αvβ3. These results indicate that HRG is regulating αvβ3

levels as well as αvβ3-triggered signaling through its downstream effector, CYR61, in highly invasive breast cancer cells. Altogether, the data presented here provide evidence of a

CYR61-regulatory role on αvβ3 integrin expression in the modulation of uncontrolled growth of HRG-overexpressing breast carcinomas. This work supports additional studies concerning the use

of integrin antagonists as dual therapeutic agents in breast cancer, targeting both, endothelial and tumor cells. Access through your institution Buy or subscribe This is a preview of

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ONCOGENIC ACTIVITIES OF INTEGRINS AND TGF-Β IN TRIPLE-NEGATIVE BREAST CANCER PROGRESSION AND METASTASIS Article Open access 19 September 2024 INTEGRIN REGULATION BY TISSUE FACTOR PROMOTES

CANCER STEMNESS AND METASTATIC DISSEMINATION IN BREAST CANCER Article 21 October 2022 UNDERSTANDING THE ROLE OF INTEGRINS IN BREAST CANCER INVASION, METASTASIS, ANGIOGENESIS, AND DRUG

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22, 761–768. Download references ACKNOWLEDGEMENTS The authors would like to thank Miaw-Shei Tsai for the generation of the Cyr61 antisense cells and Dr David Griggs for providing the RGD

peptidomimetic agents. This work was supported by the breast cancer Auxiliary program at the Evanston Northwestern Healthcare Research Institute (RL) and the NIH award number

NIDDK-RO1-0490490 to RL. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Medicine, Breast Cancer Translational Research Laboratory, Evanston Northwestern Healthcare Research

Institute, 1001 University place, Evanston, IL, 60201, USA Luciano Vellon, Javier A Menendez & Ruth Lupu * Northwestern University Feinberg School of Medicine, Chicago, IL, USA Luciano

Vellon, Javier A Menendez & Ruth Lupu Authors * Luciano Vellon View author publications You can also search for this author inPubMed Google Scholar * Javier A Menendez View author

publications You can also search for this author inPubMed Google Scholar * Ruth Lupu View author publications You can also search for this author inPubMed Google Scholar RIGHTS AND

PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Vellon, L., Menendez, J. & Lupu, R. αVβ3 integrin regulates heregulin (HRG)-induced cell proliferation and

survival in breast cancer. _Oncogene_ 24, 3759–3773 (2005). https://doi.org/10.1038/sj.onc.1208452 Download citation * Received: 14 September 2004 * Revised: 08 December 2004 * Accepted: 08

December 2004 * Published: 14 March 2005 * Issue Date: 26 May 2005 * DOI: https://doi.org/10.1038/sj.onc.1208452 SHARE THIS ARTICLE Anyone you share the following link with will be able to

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initiative KEYWORDS * Heregulin * αVβ3 * integrins * S-247 * breast cancer