researchers identify how her2 becomes particularly invasive;culprit becomesnew target

[Lani]

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."

[AlaskaAngel]

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?

[Lien]

Interesting study and good questions, Alaska Angel. How would we find a researcher who can respond to these questions?

Jacqueline

[Jackie07]

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

• Nat Rev Cancer. 2012 Jan;12(1):2.

[Mtngrl]

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.

[Hopeful]

apparent connection(s) between inflammation, insulin, estrogen and breast (and other hormone-driven) cancers

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

[AlaskaAngel]

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