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Old 05-25-2012, 03:31 PM   #1
Lani
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another important player in her2 story IDd--role in herceptin resistance

University of Texas M. D. Anderson Cancer Center
Skp2 activates cancer-promoting, glucose-processing Akt

E3 ligase's role makes it target for defeating Herceptin resistance, stifling cancer's preferred diet

HOUSTON –HER2 and its epidermal growth factor receptor cousins mobilize a specialized protein to activate a major player in cancer development and sugar metabolism, scientists report in the May 25 issue of Cell.

This chain of events, the scientists found, promotes Herceptin resistance in breast cancer and activation of glucose metabolism (glycolysis), which cancer cells primarily rely on to fuel their growth and survive.

Their research focused on Skp2 E3 ligase, a protein that binds to and tags other proteins with molecules called ubiquitins, in this case to activate the Akt kinase.

"We discovered a novel function of Skp2 E3 ligase that makes it an important player in cancer development and also identified a crucial role for it as a regulator of the glycolysis pathway," said senior author Hui-Kuan Lin, Ph.D., associate professor in MD Anderson's Department of Molecular and Cellular Oncology.

"This is potentially important for understanding and addressing Herceptin resistance in breast cancer," Lin said. "The effect on glucose metabolism also could have implications for other types of solid tumor cancers, including prostate, because they rely so heavily on glycolysis."

The team also found that Skp2 overexpression is associated with poor prognosis for breast cancer patients and its spread to other organs.

Lin and colleagues are studying potential inhibitors of Skp2 that might be developed for treatment.

The EGFR family of proteins includes HER2, which abundantly coats cancer cells in about a third of breast cancers, making these tumors prime targets for the targeted drug Herceptin.

Fundamental discovery about Akt activation

The Akt kinase relays signals by growth factors from outside of the cell into the cell. It regulates cell profliferation and survival, metabolism and tumor development, the authors noted.

To do its work, whether normal or oncogenic signaling, it must move from the cytosol to the plasma membrane. To do that, Lin and colleagues had previously shown that Akt must be ubiquitinated – and those ubiquitins must be attached in a specific chain formation, the K63-linked polyubiquitin chains.

That earlier finding involved the insulin-like growth factor receptor (IGF-1) and a different E3 ligase. "Finding that the epidermal growth factor receptors also ubiquitinate Akt, and that they do so through the Skp2 E3 ligase, was quite unexpected," Lin said.

Finding two paths to ubiquitination implies that there might be more, Lin said.

Regulating cancer's energy engine

Tumor cells evolve to rely mainly on glucose processing to generate energy, grow and thrive. They increase glucose uptake and glycolysis, a process that doesn't involve oxygen and occurs in the cell's cytosol. Non-cancerous cells rely more heavily on oxygen-based metabolism of fatty acids and other nutrients in the cell's mitochondria. This difference is called the Warburg Effect.

In a series of experiments, the researchers blocked Skp2 expression and found:

Suppression of glucose uptake and glycolysis in breast cancer cell lines.
Reduction of tumor size and glucose uptake in a mouse model of HER2-expressing breast cancer.
Steep declines in the expression of glucose-transporter Glut1. Cells with Skp2 produced more Glut1 when induced by epidermal growth factor signaling. Akt activates Glut1.
Reduced Akt activation, Glut1 expression and tumor growth plus extended survival in mice genetically engineered to develop breast cancer and metastasis.
Poor prognosis, Herceptin resistance

The team analyzed 213 cases of breast cancer treated with modified radical mastectomy but no chemotherapy or radiation. Of these, 80 were HER2-positive. In these tumors Skp2 expression was correlated with:

Adverse prognostic factors such as cancer stage, primary tumor status and lymph node metastasis.
Increased activation of Akt.
A multivariable analyses of prognostic factors showed Skp2 overexpression to be a significant factor affecting metastasis-free survival for HER2-positive breast cancer patients.

No prognostic role was found for Skp2 expression among patients with HER2-negative disease.

HER2-positive breast cancer patients can develop resistance to Herceptin treatment, the researchers noted, and some encounter this problem right at the start.

Knocking down Skp2 made cancer cell lines more susceptible to Herceptin, stifling cancer proliferation. In another mouse model, Herceptin by itself inhibited tumor growth but did not shrink tumors. With Skp2 inhibited, Herceptin treatment caused the tumors to nearly vanish in 22 days.

This sensitivity was blocked when the scientists overexpressed Akt in Skp2-silenced cancer cells.

Overall, the team's findings indicate that blocking Skp2 might inhibit glycolysis and that targeting glycolysis could be an important approach to cancer treatment, Lin said.

###
Co-authors with Lin are first author Chia-Hsin Chan, Ph.D., Wei-Lei Yang, Yuan Gao, Szu-Wei Lee, Zizhen Feng, Dihua Yu, M.D., Ph.D., Dos Sarbassov, Ph.D., and Mien-Chie Hung, Ph.D., all of MD Anderson's Department of Molecular and Cellular Oncology; Leo Flores of MD Anderson's Department of Experimental Diagnostic Imaging; Yiping Shao, Ph.D., and John Hazle, Ph.D., of MD Anderson's Department of Imaging Physics; Chien-Feng Li, M.D., of Chi-Mei Foundational Medical Center in Tainan, Taiwan, and with Kelvin Tsai, M.D., also of the National Institute of Cancer Research in Tainan; Hsuan-Ying Huang, M.D., Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Taiwan; Wenyi Wei, Ph.D., Beth Israel Deaconess Medical Center and Harvard Medical School; and Keiichi Nakayama, M.D., Ph.D. Medical Institute of Bioregulations, Kyushu University, Fukuoka, Japan.
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Old 05-25-2012, 03:48 PM   #2
DeenaH
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Re: another important player in her2 story IDd--role in herceptin resistance

Thank you for always posting these articles Lani! I find it hard for my chemo brain to understand them a lot of the time though.

In laymen's terms, what does this mean? I thought there were already AKT inhibitors in trials? I believe my chemosensitivity test showed that my cancer was sensitive to them. My cancer has been resistant to Herceptin from the start, so this concept interests me greatly. I just wish things moved along faster with research like this!
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March 2010: Diagnosed with Stage IIIC IDC with axillary, mammary and suplaclavicular node involvement. ER/PR -, HER2+++. 7cm tumor in right breast.
April 2010: Started neoadjuvent chemo. 4 DD A/C every 2 weeks, 4 DD Taxotere every 3 weeks with Herceptin weekly.
August 2010: Finished chemo!
August 20, 2010: PET/CT showed no cancer in any nodes, and only a little uptake to the breast.
September 9, 2010: Bilateral mastectomy with immediate reconstruction with implants and Alloderm.
September 16, 2010: Pathology report showed 18/51 positive axillary nodes, 3.2cm tumor. Granual sized cancer found in the fatty tissue between levels 1 and 2.
October 19, 2010: CT showed several spots on lungs and 1 spot on liver. Liver spot is 2mm, lung spots range from 2mm to 4mm. We don't know if they are cancer or not.
12/15/10: Brain MRI clear
1/7/11: PET/CT
1/13/11: Recurrence in lungs. Start Tykerb
5/13/11: Progression in lungs
6/3/11: Lung surgery to get tumors for chemosensitivity testing.
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Old 05-25-2012, 09:07 PM   #3
Rich66
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Re: another important player in her2 story IDd--role in herceptin resistance

http://www.ncbi.nlm.nih.gov/pubmed?t...p2%20Metformin

Quote:
Metformin also decreased the levels of oncogenic proteins Skp2 and β-Trcp.
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Old 05-25-2012, 09:19 PM   #4
StephN
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Wink Re: another important player in her2 story IDd--role in herceptin resistance

Does this boil down to controlling simple sugar intake?

How does one make the following happen in real life?

"Knocking down Skp2 made cancer cell lines more susceptible to Herceptin, stifling cancer proliferation. In another mouse model, Herceptin by itself inhibited tumor growth but did not shrink tumors. With Skp2 inhibited, Herceptin treatment caused the tumors to nearly vanish in 22 days."
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"When I hear music, I fear no danger. I am invulnerable. I see no foe. I am related to the earliest times, and to the latest." H.D. Thoreau
Live in the moment.

MY STORY SO FAR ~~~~
Found suspicious lump 9/2000
Lumpectomy, then node dissection and port placement
Stage IIB, 8 pos nodes of 18, Grade 3, ER & PR -
Adriamycin 12 weekly, taxotere 4 rounds
36 rads - very little burning
3 mos after rads liver full of tumors, Stage IV Jan 2002, one spot on sternum
Weekly Taxol, Navelbine, Herceptin for 27 rounds to NED!
2003 & 2004 no active disease - 3 weekly Herceptin + Zometa
Jan 2005 two mets to brain - Gamma Knife on Jan 18
All clear until treated cerebellum spot showing activity on Jan 2006 brain MRI & brain PET
Brain surgery on Feb 9, 2006 - no cancer, 100% radiation necrosis - tumor was still dying
Continue as NED while on Herceptin & quarterly Zometa
Fall-2006 - off Zometa - watching one small brain spot (scar?)
2007 - spot/scar in brain stable - finished anticoagulation therapy for clot along my port-a-catheter - 3 angioplasties to unblock vena cava
2008 - Brain and body still NED! Port removed and scans in Dec.
Dec 2008 - stop Herceptin - Vaccine Trial at U of W begun in Oct. of 2011
STILL NED everywhere in Feb 2014 - on wing & prayer
7/14 - Started twice yearly Zometa for my bones
Jan. 2015 checkup still shows NED
2015 Neuropathy in feet - otherwise all OK - still NED.
Same news for 2016 and all of 2017.
Nov of 2017 - had small skin cancer removed from my face. Will have Zometa end of Jan. 2018.
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Old 05-26-2012, 05:25 PM   #5
Mandamoo
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Re: another important player in her2 story IDd--role in herceptin resistance

As one who has been "perception resistant" from the get go this is very interesting. What are the real life implications?

Rich - I have been told that Metformin is only helpful for diabetic patients with cancer. What do you think? I have none of the typical pre diabetic characteristics either if that's any indicator.

Steph - I have cut sugar out of my diet - maybe this will help?

Loving these new insights into her2 especially, perception resistance.
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Amanda xx
40 year old Mum to three gorgeous kids - son 5 and daughters 8 and 11
Wife to my wonderfully supportive husband of 17 years!
22 February 2011 - Diagnosed Early Breast Cancer IDBC Stage2b (ER/PR -ve, Her2+ve +++) - 38 years old
(L) skin sparing mastectomy with tissue expander, axilla clearance (2/14 affected) clear margins.
Fec*3, Taxotere and herceptin*2 - stopped due to secondary diagnosis

June 24 2011 Stage IV - Skin met, axilla node, multiple lung lesions

Bolero3 trial - Navelbine, Hereptin weekly, daily Everolimus/Placebo
February 2012 - July 2012 Tykerb and Xeloda - skin mets resolved, Lungs initially dramatically reduced but growing again
August 2012 (turn 40!) tykerb and herceptin (denied compassionate use of TDM1) while holidaying in Italy!
September 2012 - January 2013 TDM1 as part of the Th3resa trial - lymph nodes resolved, lungs slowly progressing.
January 2013 - herceptin, carboplatin and Perjeta (compassionate access)
April 2013 - Some progression in lungs and lymph nodes - Abraxane, Herceptin and Perjeta
July 2013 - mixed response - dramatic reduction of most lung disease, progression of smaller lung nodules and cervical and hilar nodes - ? Add avastin.
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Old 05-27-2012, 05:50 PM   #6
Rich66
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Re: another important player in her2 story IDd--role in herceptin resistance

Amanda,
My personal perspective is that Metformin is showing relevance beyond diabetics. It is being investigated in context of overall longevity as well as regarding cancer patients.

http://her2support.org/vbulletin/showthread.php?t=39740
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Old 05-27-2012, 06:07 PM   #7
Rolepaul
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Re: another important player in her2 story IDd--role in herceptin resistance

Lani has impressed me with her knowledge. It is great to have someone with the ability to track down research of this detail. It helps people like me to figure out the best path forward for my wife Nina. I hope to be half as good as Lani in the information I give out. Most of my contacts are in the pharmaceutical manufacturing business with a bunch in process development as well. Getting the hard core researchers to get information from is what we can rely on Lani for. Thanks for all you do. I mostly focus on a specific set of patients that my wife is a member of, HER+, Er-, PR-. In particular, I look at Brain/Spine mets. Unfortunately, I think this will be an area that will need more investigation because of the inability of some drugs to get through the blood brain barrier. I hope that I can get more info out in the future.
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Old 05-28-2012, 01:32 PM   #8
suzan w
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Re: another important player in her2 story IDd--role in herceptin resistance

Sugar is such a tricky beast. I have just read that now sugar is being implicated in Bad Cholesterol and not so much the fats, etc. That sugar forms plaque-like gunk that clogs arteries...fat makes artery walls smooth so gunk can safely flow....and it seems that sugar is in just about everything in one form or another.
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Suzan W.
age 54 at diagnosis
5/05 suspicious mammogram-left breast
5/05 biopsy-invasive lobular carcinoma with LCIS,8mm tumor,stage 1 grade 2, ER+ PR+ Her2+++
6/14/05 bilateral mastectomy, node neg. all scans neg.
Oncotype DX-high risk
8/05-10/05 4 rounds A/C
10/05 -10/06 1 yr. herceptin
arimidex-5 years
2/14/08 started daily self administered injections..FORTEO for severe osteoporosis
7/28/09 BRCA 1 negative BRCA2 POSITIVE
8/17/09 prophylactic salpingo-oophorectomy
10/15/10 last FORTEOinjection
RECLAST infusion(ostoeporosis)
6/14/10 5 year cancerversary!
8/2010-18%increase in bone density!
no further treatments
Oncologist says, "Go do the Happy Dance"
I say,"What a long strange trip its been"
'One day at a time'
6-14-2015. 10 YEAR CANCERVERSARY!
7-16 to 9-16. Extensive (and expensive) dental work done to save teeth. Damage from osteoporosis and chemo and long term bisphosphonate use
6-14-16. 11 YEAR CANCERVERSARY!!
7-20-16 Prolia injection for severe osteoporosis
2 days later, massive hive outbreak. This led to an eventual dx of Chronic Ideopathic Urticaria, an auto-immune disease from HELL.
6-14-17 12 YEAR CANCERVERSARY!!
still suffering from CIU. 4 hospitilizations in the past year

as of today, 10-31-17 in remission from CIU and still, CANCER FREE!!!
6-14-18 13 YEAR CANCERVERSARY!! NED!!
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