Phosphoinositide 3-kinase signaling is critical for ErbB3-driven breast cancer cell motility and metastasis.

Many malignancies show increased expression of the epidermal growth factor (EGF) receptor family member ErbB3 (HER3). ErbB3 binds heregulin ß-1 (HRGß1) and forms a heterodimer with other ErbB family members, such as ErbB2 (HER2) or EGF receptor (EGFR; HER1), enhancing phosphorylation of specific C-terminal tyrosine residues and activation of downstream signaling pathways. ErbB3 contains six YXXM motifs that bind the p85 subunit of phosphoinositide 3 (PI3)-kinase. Previous studies demonstrated that overexpression of ErbB3 in mammary tumor cells can significantly enhance chemotaxis to HRGß1 and overall metastatic potential. We tested the hypothesis that ErbB3-mediated PI3-kinase signaling is critical for heregulin-induced motility, and therefore crucial for ErbB3-mediated invasion, intravasation and metastasis. The tyrosines in the six YXXM motifs on the ErbB3 C-terminus were replaced with phenylalanine. In contrast to overexpression of the wild-type ErbB3, overexpression of the mutant ErbB3 did not enhance chemotaxis towards HRGß1 in vitro or in vivo. We also observed reduced tumor cell motility in the primary tumor by multiphoton microscopy, as well as a dramatically reduced ability of these cells to cross the endothelium and intravasate into the circulation. Moreover, whereas mutation of the ErbB3 C-terminus had no effect on tumor growth, it had a dramatic effect on spontaneous metastatic potential. Treatment with the PI3-kinase inhibitor PIK-75 similarly inhibited motility and invasion in vitro and in vivo. Our results indicate that stimulation of the early metastatic steps of motility and invasion by ErbB3 requires activation of the PI3-kinase pathway by the ErbB3 receptor.

A disorder of sympathomimetic amines leading to increased vascular permeability may be the etiologic factor in various treatment refractory health problems in women.

There is an evidence that increased capillary permeability in the standing position is related to a deficit in the sympathetic nervous system. The leakage of this fluid leads to various clinical conditions which frequently puzzle the consulting physician because despite the frequency of this condition intelligent physicians and patients are unaware of the cause of their condition. One of the most common manifestations is the inability to lose weight despite proper dieting. A randomized study comparing the efficacy of a diuretic, a converting enzyme inhibitor, spironolactone and a sympathomimetic amine on weight loss in diet refractory women found that only the latter in the form of dextroamphetamine sulfate demonstrated significant weight reduction over a six month time span. In fact, the dextroamphetamine sulfate proved effective when given in the next 6 months to the three groups failing to respond for the first 6 months. The diagnosis of a deficit in sympathomimetic amines is established by demonstrating an abnormal clearance of a water load in the erect position and exclusion of other conditions that are associated with an abnormal free water clearance, e.g., hypothyroidism, renal or liver disease or congestive heart failure. The original definition of an abnormal water load test was excretion of <55% of a 1500 ml water load in 6h but we found that <75% defines a greater population who suffer from this problem. There are several conditions that have proven refractory to conventional theory that respond quickly and effectively to sympathomimetic amines. There have been many anecdotal reports of relieving interactable pain syndromes quickly and efficiently with sympathomimetic amine theory, despite failure with a multitude of other therapies. These include interstitial cystitis and pelvic pain that was attributed to endometriosis, gastrointestinal pain including esophagitis and gastroparesis, headaches, joint pain, fibromyalgia, and carpal tunnel syndrome. It is not clear if the improvement in pain is related to a decrease in fluid retention or a direct effect of the sympathomimetic amines on the sympathetic nervous system. Sympathomimetic amine theory has helped other conditions besides pain, e.g., chronic fatigue, vasomotor symptoms in young women not associated with decreased ovarian egg reserve, and chronic urticaria resistant to all other therapies. Thus, these studies strongly suggest that physicians be aware of this condition involving a deficit in the sympathetic nervous system when faced with various enigmatic complaints especially if standard therapy has not proven effective.

Sympathomimetic amine therapy may improve refractory gastroparesis similar to its effect on chronic pelvic pain--case report.

PURPOSE: To determine if treatment with sympathomimetic amines can effectively treat gastroparesis that was refractory to other medical therapy. METHODS: After failing a water load test, a 29-year-old female was treated with 20 mg/day of dextroamphetamine sulfate. RESULTS: After several weeks of therapy she noted that most of her symptoms of gastroparesis subsided and she has remained symptom free for eight months. CONCLUSIONS: Similar to its beneficial effect on chronic pelvic pain of both bladder and non bladder origin, refractory weight gain, esophageal pain, chronic fatigue syndrome, headaches and vasomotor symptoms, sympathomimetic amine therapy can also effectively treat gastroparesis refractory to other medical therapies at least in some cases.

Marked improvement of intractable arthritic pain in a woman with rheumatoid arthritis with sympathomimetic amine treatment despite previous failure with standard therapy and possible implications for last trimester unexplained fetal demise--case report.

PURPOSE: To determine if sympathomimetic amine treatment could alleviate severe arthritic pain and fatigue associated with rheumatoid arthritis which was refractory to other medical therapy in a patient with a history of unexplained last trimester fetal demise and unexplained cessation of fetal movement and acidosis. METHODS: A 32-year-old female was treated with 10 mg of dextroamphetamine sulfate daily after failing to gain relief with standard therapy for rheumatoid arthritis. RESULTS: After several weeks of therapy the patient noticed fewer flare ups of arthritic pain and a marked improvement in her fatigue. Six months on the sympathomimetic amines she noticed improvement in her ability to carry out everyday activities, less flare ups, and increased energy. CONCLUSIONS: Sympathomimetic amines as demonstrated in this case report can effectively relieve joint pain when conventional therapies for rheumatoid arthritis fail, at least if the water load test is abnormal. Perhaps this therapy could prove beneficial in inhibiting chorionic villitis which can cause fetal death.