[Rich66]

Liked this part also:

Metformin and estradiol
Active AMPK inhibits the expression of the aromatase gene in breast adipose tissue by decreasing the local production of estrogen [93]. Furthermore, obese patients with breast cancer exhibit a higher expression of this gene and higher levels of estrogen in breast tissue as a result of increased plasma leptin synthesis, which is caused by obesity. Leptin inhibits AMPK by increasing the expression of aromatase; however, adiponectin activates AMPK. Therefore, metformin-based treatments aimed at activating AMPK and restoring the leptin/adiponectin axis may decrease the occurrence of breast cancer in obese patients.

At this point Metformin appears to simultaneously target mechanisms involved with triple negative, ER+ and Her2+ breast cancer as well as other cancers.


A potent her2 portion of the paper:

it is worth mentioning that metformin acts synergistically with the anti-HER2 monoclonal antibody trastuzumab (Herceptin™) to eliminate stem/progenitor cell populations in HER2-gene amplified breast carcinoma cells growing as mammospheres [108]. Moreover, metformin treatment efficiently reverses secondary resistance of HER2-overexpressing cancer cells to the dual HER1/HER2 tyrosine kinase inhibitor lapatinib (Tykerb™) by suppressing pro-survival pathways (i.e., the anti-apoptotic protein survivin) [109-111].
In HER2-positive tumors, metformin has a dual effect: 1) inhibiting the activity/expression of the HER2 onco-tyrosine kinase and 2) blocking the action of mTOR, a possible mechanism of resistance to trastuzumab [88, 112]. Additionally, by decreasing the levels of circulating insulin and IGF, activation of the IGFR pathway will be avoided. Because transactivation of the IGFR pathway is a well-recognized mechanism underlying de novo (i.e., primary) [113] and acquired (i.e., secondary) [114, 115] resistance to anti-HER2 therapies, metformin’s ability to simultaneously target HER2, while preventing increased IGF-IR signaling may represent a potential therapeutic tool in breast carcinomas resistant to HER2-directed therapy. In support of this, a recently conducted pre-clinical study with trastuzumab-sensitive parental breast cancer cell lines (i.e., BT474 and SKBR3) and trastuzumab-resistant breast cancer sublines (i.e., BT-474-HR20 and SKBR3-pool2) showed that metformin treatment causes significantly more inhibition of proliferation and clonogenicity in trastuzumab-resistant sublines via disruption of HER2/IGF-IR complexes (which are solely present in the resistant sublines) [116]. Importantly, this effect occurred without altering HER2 expression or reduction of IGF-IR expression or activity in the trastuzumab-resistant but not in the sensitive breast cancer cells. The activity of AMPK in cardiac cells is associated with stress-induced survival in response to cytokines or energy depletion. Thus, the concurrent blockage of oncogenic receptors such as HER2, while activating AMPK-related catabolic pathways with metformin would be a highly efficacious therapy to prevent, delay and/or reverse resistance to the HER2 inhibitor while decreasing the risk of cardiomyopathy [109, 117].