Dr. Slamon et al have done it again--found a new target in her2+ br cancers (against
 

which antibodies can be directed to treat those resistant to herceptin, or better still to treat with initially, combined with herceptin, to PREVENT herceptin resistance

Cancer Res. 2010 Jun 15. [Epub ahead of print]
FOXO1A Is a Target for HER2-Overexpressing Breast Tumors.
Wu Y, Shang X, Sarkissyan M, Slamon D, Vadgama JV.

Authors' Affiliations: Divisions of Cancer Research and Training and Hematology/Oncology, Department of Medicine, Charles R. Drew University of Medicine and Science; University of California at Los Angeles David Geffen School of Medicine, Los Angeles, California.
Abstract
Trastuzumab treatment has improved the overall survival of HER2-overexpressing breast cancer patients. However, many of these patients will eventually become resistant to treatment. The mechanisms that contribute to resistance to trastuzumab are unknown. In this study, we tested the hypothesis that targeting of the FKHR transcription factor FOXO1A in HER2-overexpressing breast tumor cells can overcome the trastuzumab resistance in vitro. We have shown that overexpression of HER2 leads to activation of phosphatidylinositol 3-kinase (PI3K)/Akt pathway and subsequent inactivation of FOXO1A in HER2-overexpressing breast cancer cells SKBR3, BT474, and MCF7-HER2. In wild-type SKBR3 and BT474 cells, trastuzumab downregulates active Akt and increases FOXO1A expression that leads to increase in p27(kip1) and decrease in cyclin D1 and finally inhibits cell proliferation. In contrast, the effect of trastuzumab was eliminated by the reduction of FOXO1A in HER2-overexpressing cells with constitutively active Akt1 (SKBR3/AA28 and BT474/AA9). The downregulation of FOXO1A resulted in nuclear export of p27(kip1). Blocking the constitutively active Akt by a specific Akt/protein kinase B signaling inhibitor-2 (API-2) significantly increased FOXO1A expression and rendered the cells more responsive to trastuzumab-induced growth inhibition. Reactivation of FOXO1A by stable or transient transfection also restored the growth-inhibitory effects of trastuzumab in SKBR3/AA28, BT474/AA9, and MCF7-HER2 cells. Knocking down FOXO1A by small interfering RNA resulted in reducing trastuzumab-induced growth inhibition. In summary, trastuzumab can inhibit proliferation of HER2-overexpressing breast cancer cells by reactivating FOXO1A through inhibition of the PI3K/Akt pathway. FOXO1A may therefore serve as a target for HER2-overexpressing breast tumors. Cancer Res; 70(13); OF1-11. (c)2010 AACR.

PMID: 20551062

Re: Dr. Slamon et al have done it again--found a new target in her2+ br cancers (agai
 

Exciting news...thanks for posting this Lani.

Chelee

Re: Dr. Slamon et al have done it again--found a new target in her2+ br cancers (agai
 

God has blessed us with researchers like Dr. Slamon who is always searching for the answers.

This is very promising..


each day we get a little bit closer.
Jean

Re: Dr. Slamon et al have done it again--found a new target in her2+ br cancers (agai
 

Not that I could understand much of the report, but I'm thinking this is very good news. Thanks for posting Lani and keep at it Slamon and Co. And hurry please!

Re: Dr. Slamon et al have done it again--found a new target in her2+ br cancers (agai
 

"trastuzumab can inhibit proliferation of HER2-overexpressing breast cancer cells by reactivating FOXO1A through inhibition of the PI3K/Akt pathway."

Good thing there are currently available ways to inhibit PI3k/Akt:

Zoledronate Acid (Zometa)
Tamoxifen
Green Tea
IP6
Honokiol
Apigenin

Re: Dr. Slamon et al have done it again--found a new target in her2+ br cancers (agai
 

"In this study, we tested the hypothesis that targeting of the FKHR transcription factor..."

Well if I've said once I've said a thousand times, we should kill those little FKHRs.

LANI - Great post, and Rich, thanks for the list of PI3k etc inhibitors.

Flori

Re: Dr. Slamon et al have done it again--found a new target in her2+ br cancers (agai
 

Lani,
Thanks for posting!
karen