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03-29-2012, 07:39 PM
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#1
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Senior Member
Join Date: Mar 2006
Posts: 4,778
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researchers identify how her2 becomes particularly invasive;culprit becomesnew target
Public release date: 29-Mar-2012
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Contact: Elisabeth (Lisa) Lyons
elyons@cell.com
617-386-2121
Cell Press
Researchers identify mechanism that makes breast cancer invasive
A new study has identified a key mechanism that causes breast cancer to spread. The research, published by Cell Press on March 30th in the journal Molecular Cell, enhances our knowledge about the signals that drive cancer metastasis and identifies new therapeutic targets for a lethal form of invasive breast cancer that is notoriously resistant to treatment.
Amplification of the gene for ErbB2 has been linked with aggressive forms of breast cancer and is associated with a poor outcome. Although ErbB2-positive breast cancers are routinely treated with chemotherapy and the ErbB2-targeted drug trastuzumab (Herceptin), this treatment often fails. "Nearly half of breast cancers with high ErbB2 expression are either initially non-responsive or eventually develop resistance to trastuzumab," explains senior study author, Dr. Tuula Kallunki, from the Danish Cancer Society Research Center. "Therefore, a better understanding of the molecular basis of ErbB2-induced malignancy is critical for further development of targeted treatments."
In the current study, Dr. Kallunki and colleagues discovered that ErbB2 induces expression of proteins called cathepsins. Previous work has linked cathepsins with metastasis of pancreatic cancer, specifically with tumor cell invasion of surrounding tissues and with the establishment of tumor blood supply. Using a three-dimensional model system to study ErbB2-induced cellular invasion, the researchers demonstrated that inhibition of cathepsins prevented ErbB2-driven breast cancer invasion. They went on to identify components of the complex signaling network linking ErbB2 and cathepsin expression with cancer invasiveness.
Taken together, the results demonstrate that the invasive behavior of ErbB2-positive cancer cells is dependent on cathepsin activity and uncover a molecular link between ErbB2 and breast cancer invasion. "Our work has introduced a cellular model system to study ErbB2-induced invasion and identified an invasion-promoting signaling network," concludes Dr. Kallunki. "In addition, our findings provide several potential therapeutic targets against ErbB2-driven invasive cancers."
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Rafn et al.: "ErbB2-driven breast cancer cell invasion depends on a complex signaling network activating myeloid zinc finger-1-dependent cathepsin B expression."
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04-02-2012, 11:29 AM
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#2
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Senior Member
Join Date: Sep 2005
Location: Alaska
Posts: 2,018
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Re: researchers identify how her2 becomes particularly invasive;culprit becomesnew ta
I am wondering about the chain of events that occurs for HER2 patients and its influence on cathepsin production.
If inflammation levels are increased for those with HER2 bc, is the cathepsin release part of the natural immune system defense response to inflammation?
If the release of cathepsins are a natural immune response, then given that chemotherapy significantly increases inflammation (which has to be masked for tolerance through the use of more and more effective anti-emetics to counteract more and more inflammatory chemotherapies), is chemotherapy in part increasing the likelihood for mets because of an increased cathepsin production in response to the significant inflammation brought about by chemotherapy?
In other words, is chemo sometimes working to kill those cancer cells that happen not to be resistant to the particular chemo used, but is the chemo simultaneously also in effect encouraging mets?
Would use of trastuzumab alone reduce the likelihood of mets, by causing less inflammation repeatedly during treatment than chemo plus trastuzumab? Or perhaps use of low-dose continuous chemotherapy, and then trastuzumab?
Is chemotherapy plus trastuzumab achieving more initial success with getting HER2 positive patients past the high-risk first 2 or 3 years, but only delaying recurrence by encouraging mets because of the inflammation response to chemotherapy and the release of cathepsins?
I'm not saying this IS what is happening.
Would there be increased cathepsin release for those who have more inflammation due to increased weight prior to treatment and/or after treatment?
__________________
Dx 2002 age 51
bc for granny, aunt, cousin, sister, mother.
ER+/PR+/HER2+++, grade 3
IDC 1.9 cm, some DCIS, Stage 1, Grade 3
Lumpectomy, CAFx6 (no blood boosters), IMRT rads, 1 3/4 yr tamoxifen
Rads necrosis
BRCA 1 & 2 negative
Trials: Early detection OVCA; 2004 low-dose testosterone for bc survivors
Diet: Primarily vegetarian organic; metformin (no diabetes), vitamin D3
Exercise: 7 days a week, 1 hr/day
No trastuzumab, no taxane, no AI
NED
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04-03-2012, 02:05 AM
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#3
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Senior Member
Join Date: May 2006
Location: Haarlem, the Netherlands
Posts: 835
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Re: researchers identify how her2 becomes particularly invasive;culprit becomesnew ta
Interesting study and good questions, Alaska Angel. How would we find a researcher who can respond to these questions?
Jacqueline
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Diagnosed age 44, January 2004, 0.7 cm IDC & DCIS. Stage 1, grade 3, ER/PR pos. HER2 pos. clear margins, no nodes. SNB. 35 rads. On Zoladex and Armidex since Dec. 2004. Stopped Zoladex/Arimidex sept 2009 Still taking mistletoe shots (CAM therapy) Doing fine.
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04-03-2012, 09:42 AM
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#4
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Senior Member
Join Date: Jan 2008
Location: "Love never fails."
Posts: 5,808
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Re: researchers identify how her2 becomes particularly invasive;culprit becomesnew ta
Another article (abstract) on the subject:
Genes Dev. 2011 Dec 1;25(23):2465-79.
Macrophages and cathepsin proteases blunt chemotherapeutic response in breast cancer.
Shree T, Olson OC, Elie BT, Kester JC, Garfall AL, Simpson K, Bell-McGuinn KM, Zabor EC, Brogi E, Joyce JA.
Source
Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Abstract
The microenvironment is known to critically modulate tumor progression, yet its role in regulating treatment response is poorly understood. Here we found increased macrophage infiltration and cathepsin protease levels in mammary tumors following paclitaxel (Taxol) chemotherapy.
Cathepsin-expressing macrophages protected against Taxol-induced tumor cell death in coculture, an effect fully reversed by cathepsin inhibition and mediated partially by cathepsins B and S. Macrophages were also found to protect against tumor cell death induced by additional chemotherapeutics, specifically etoposide and doxorubicin.
Combining Taxol with cathepsin inhibition in vivo significantly enhanced efficacy against primary and metastatic tumors, supporting the therapeutic relevance of this effect.
Additionally incorporating continuous low-dose cyclophosphamide dramatically impaired tumor growth and metastasis and improved survival.
This study highlights the importance of integrated targeting of the tumor and its microenvironment and implicates macrophages and cathepsins in blunting chemotherapeutic response.
Comment in
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Jackie07
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3-11 Appendectomy - visually O.K., a lot of puss. Final path result - not cancer.
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04-03-2012, 10:12 AM
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#5
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Senior Member
Join Date: May 2011
Location: Denver, CO
Posts: 1,427
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Re: researchers identify how her2 becomes particularly invasive;culprit becomesnew ta
AA,
As always, I appreciate you sharing your questions and analysis.
I'm intrigued by the apparent connection(s) between inflammation, insulin, estrogen and breast (and other hormone-driven) cancers.
__________________
Amy
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4/19/11 Diagnosed invasive ductal carcinoma in left breast; 2.3 cm tumor, 1 axillary lymph node, weakly ER+, HER2+++
4/29/11 CT scan shows suspicious lesions on liver and lungs
5/17/11 liver biopsy
5/24/11 liver met confirmed--Stage IV at diagnosis
5/27/11 Begin weekly Taxol & Herceptin for 3 months (standard of care at the time of my DX)
7/18/11 Switch to weekly Abraxane & Herceptin due to Taxol allergy
8/29/11 CT scan shows no new lesions & old lesions shrinking
9/27/11 Finish Abraxane. Start Herceptin every 3 weeks. Begin taking Arimidex
10/17/11--Brain MRI--No Brain mets
12/5/11 PET scan--Almost NED
5/15/12 PET scan shows progression-breast/chest/spine (one vertebra)
5/22/12 Stop taking Arimidex; stay on Herceptin
6/11/12 Started Tykerb and Herceptin on clinical trial (w/no chemo)
9/24/12 CT scan--No new mets. Everything stable.
3/11/13 CT Scan--two small new possible mets and odd looking area in left lung getting larger.
4/2/13--Biopsy of suspicious area in lower left lung. Mets to lung confirmed.
4/30/13 Begin Kadcyla/TDM-1
8/16/13 PET scan "mixed," with some areas of increased uptake, but also some definite improvement, so I'll stay on TDM-1/Kadcyla.
11/11/13 Finally get hormone receptor results from lung biopsy of 4/2/13. My cancer is no longer ER positive.
11/13/13 PET scan mixed results again. We're calling it "stable." Problems breathing on exertion.
2/18/14 PET scan shows a new lesion and newly active lymph node in chest, other progression. Bye bye TDM-1.
2/28/14 Begin Herceptin/Perjeta every 3 weeks.
6/8/14 PET "mixed," with no new lesions, and everything but lower lungs improving. My breathing is better.
8/18/14 PET "mixed" again. Upper lungs & one spine met stable, lower lungs less FDG avid, original tumor more avid, one lymph node in mediastinum more avid.
9/1/14 Begin taking Xeloda one week on, one week off. Will also stay on Herceptin and Perjeta every three weeks.
12/11/14 PET Scan--no new lesions, and everything looks better than it did.
3/20/15 PET Scan--no new lesions, but lower lung lesions larger and a bit more avid.
4/13/15 Increasing Xeloda dose to 10 days on, one week off.
7/1/15 Scan "mixed" again, but suggests continuing progression. Stop Xeloda. Substitute Abraxane every 3 weeks starting 7/13.
10/28/15 PET scan shows dramatic improvement everywhere. All lesions except lower lungs have resolved; lower lungs noticeably improved.
12/18/15 Last Abraxane. Continue on Herceptin and Perjeta alone beginning 1/8/16.
1/27/16 PET scan shows cancer is stable.
5/11/16 PET scan shows uptake in some areas that were resolved on the last two scans.
6/3/16 Begin Kadcyla and Tykerb combination
6/5 - 6/23 Horrible diarrhea from K&T together. Got pneumonia.
7/15/16 Begin Kadcyla only every 3 weeks.
9/6/16 Begin radiation therapy on right lung lesion that caused the pneumonia.
10/3/16 Last of 12 radiation treatments to right lung.
11/4/16 Huffing and puffing, low O2, high heart rate, on tiniest bit of exertion. Diagnosed as radiation pneumonitis. Treated with Prednisone.
11/11/16 PET scan shows significant improvement to radiated part of right lung BUT a bunch of new lung lesions, and the bone met is getting worse.
11/22/16 Begin Eribulin and Herceptin. H every 3 weeks. E two weeks on, one week off.
3/6/17 Scan shows progression in lungs. Bone met a little better.
3/23/17 Lung biopsy. Tumor sampled is ER-, PR+ (5%), HER2+++. Getting Herceptin and Perjeta as a maintenance treatment.
5/31/17 Port placement
6/1/17 Start Navelbine & Tykerb
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04-03-2012, 11:45 AM
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#6
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Senior Member
Join Date: Aug 2006
Posts: 3,380
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Re: researchers identify how her2 becomes particularly invasive;culprit becomesnew ta
Quote:
apparent connection(s) between inflammation, insulin, estrogen and breast (and other hormone-driven) cancers
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The common connector is the endocrine system (the breast, after all, is just a specialized sweat gland). Unfortunately, endocrinologists (as AA frequently points out) have nothing to do with the treatment of bc. Since they are the docs who make a living dispensing Metformin, perhaps this will get them into bc treatment through the back door.
Hopeful
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04-03-2012, 03:18 PM
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#7
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Senior Member
Join Date: Sep 2005
Location: Alaska
Posts: 2,018
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Re: researchers identify how her2 becomes particularly invasive;culprit becomesnew ta
Thanks for sharing the interest in some of the glandular/endocrine/exocrine connections. Different areas of the body (and us) have long been isolated and treated as if they weren't part of the same endocrine system.
Hopefully they share enough of a common endocrine denominator to share the benefit of such endocrine medications as metformin.
http://health.usnews.com/health-news...p-fight-cancer
__________________
Dx 2002 age 51
bc for granny, aunt, cousin, sister, mother.
ER+/PR+/HER2+++, grade 3
IDC 1.9 cm, some DCIS, Stage 1, Grade 3
Lumpectomy, CAFx6 (no blood boosters), IMRT rads, 1 3/4 yr tamoxifen
Rads necrosis
BRCA 1 & 2 negative
Trials: Early detection OVCA; 2004 low-dose testosterone for bc survivors
Diet: Primarily vegetarian organic; metformin (no diabetes), vitamin D3
Exercise: 7 days a week, 1 hr/day
No trastuzumab, no taxane, no AI
NED
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