Lab Research Targets 'Estrogen-Receptor Positive' Breast Cancer Cells; Identifies Key

[ElaineM]

http://www.medicalnewstoday.com/articles/180248.php

[Rich66]

Here is the most recent research on pubmed by Rana (maybe explaining benefit of blocking estrogen with chemo in ER+..i.e. chemoendocrine therapy):

Cancer Res. 2010 Feb 15;70(4):1731-40. Epub 2010 Feb 9.
Estrogen Suppresses MLK3-Mediated Apoptosis Sensitivity in ER+ Breast Cancer Cells.

Rangasamy V, Mishra R, Mehrotra S, Sondarva G, Ray RS, Rao A, Chatterjee M, Rana B, Rana A.
Authors' Affiliations: Department of Pharmacology and Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois; Department of Pathology, Scott and White Hospital and Texas A&M Health Science Center, College of Medicine, Temple, Texas; Division of Biochemistry, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India; and Hines Veterans Affairs Medical Center, Hines, Illinois.
Little knowledge exists about the mechanisms by which estrogen can impede chemotherapy-induced cell death of breast cancer cells. 17beta-Estradiol (E(2)) hinders cytotoxic drug-induced cell death in estrogen receptor-positive (ER(+)) breast cancer cells. We noted that the activity of the proapoptotic mixed lineage kinase 3 (MLK3) kinase was relatively higher in estrogen receptor-negative (ER(-)) breast tumors, suggesting that E(2) might inhibit MLK3 activity. The kinase activities of MLK3 and its downstream target, c-Jun NH(2)-terminal kinase, were rapidly inhibited by E(2) in ER(+) but not in ER(-) cells. Specific knockdown of AKT1/2 prevented MLK3 inhibition by E(2), indicating that AKT mediated this event. Furthermore, MLK3 inhibition by E(2) involved phosphorylation of MLK3 Ser(674) by AKT, attenuating the proapoptotic function of MLK3. We found that a pan-MLK inhibitor (CEP-11004) limited Taxol-induced cell death and that E(2) accentuated this limitation. Taken together, our findings indicate that E(2) inhibits the proapoptotic function of MLK3 as a mechanism to limit cytotoxic drug-induced death of ER(+) breast cancer cells. Cancer Res; 70(4); 1731-40.

PMID: 20145118 [PubMed - in process]

[Hopeful]

Just thinking out loud, here:

ER+ breast cancer is generally seen as slower growing and less aggressive than ER- bc, albeit less responsive to chemotherapy. If there is a drug that transforms ER+ bc into bc that is more receptive to chemotherapy, do we not run the risk of making the cancer faster growing and more aggressive?

Hopeful

[Rich66]

Well..the classic argument typically raised against combining endocrine with chemo is that it is cytostatic, slows the cells...thus making them less susceptible to proliferation targeting chemo. The above, and numerous positive chemoendocrine examples suggest that's not the full picture. From the supplement side, does green tea appears to help Taxol despite being recognized as antiestrogenic and antiproliferative. There was an oncology researcher some years ago who referred to complimentary inihibition.
In terms of tricking cancer to be mor eactive, that's kind of how the oft maligned insulin potentiation therapy is supposed to work. The biggest risk there is if you hype up the cells and the chemo used is not effective. A serum chemosensitivity test that could be used before each treatment would be ideal to counteract that.


As crazy as speeding up cancer sounds, it's my understanding that a current cancer stem cell trial uses a "maturation" factor to make the stem cells more proliferative so Taxotere can target them. Seems like the same sensitivity issue would be there.

I have seen one older paper where it was said that metronomic dosing is compatible with endocrine since metro targets slower moving endothelial cells and doesn't care if the endocrine therapy slows down the others. A comfortable way to hang onto the old theory while gaining the benefit of combining.