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biguanide metformin in breast cancer on the supra-clinical doses of metformin consistently less than 50 µmol/L, it is easy
should proceed when considering all the employed in pre-clinical studies and, to calculate that metformin-refractory
clinical and epidemiologic evidence we therefore, they are clinically irrelevant.38 A cancer cells capable to grow in the pres-
have accumulated in the last few years. similar argumentation has been proposed ence of 10 mmol/L metformin are being
However, we should consider the fact that, to disregard our recently developed model exposed to, at least, 200-fold excess over
as with many other anti-cancer drugs used of acquired auto-resistance to metformin the recommended therapeutic levels. This
on a daily chronic basis, exposure to met- in A431 epidermoid cancer cells.39 Unlike simple calculation, however, does not
formin might be a double-edged sword if metformin-naive A431 parental cells, entirely weaken the clinico-biological rel-
more aggressive (metformin-refractory) metformin-refractory MetR10 cells dis- evance of our and other pre-clinical find-
cancer cells emerge.35 This crucial issue tinctively exhibit increased phosphoryla- ings using cultured cancer cells. Rather,
has been previously reached by some tion of IGF-1R and Vascular Endothelial it simply imposes one viewpoint, which
authors when revealing that metformin- Growth Factor Receptor (VEGFR) 3.40 focuses on the insulin-lowering mode of
induced AMPK activation may stimu- These findings suggested that disrup- action as the main mechanism by which
late neoangiogenesis and tumor growth tion of the AMPK/mTOR/S6K1 axis on metformin may influence the outcome
in xenograft models using the estrogen chronic exposure to metformin efficiently of clinical breast cancer. Jiralerspong and
receptor-negative MDA-MB-435 breast relieves negative feedback suppression colleagues observed that diabetic breast
cancer cell line. On the one hand, it was on the IGF-1R/IRS-1 axis, leading to cancer patients receiving metformin and
stressed that breast cancer is irrelevant in elevation of cell survival signals and thus neoadjuvant chemotherapy had a higher
this case because the MDA-MB-435 is counteracting the antitumor activity of rate of pathological complete responses
derived from melanoma.37 On the other metformin.40 Because the plasma concen- (pCR) than no diabetics not receiv-
hand, some authors have argued that these trations of metformin in diabetic patients ing metformin (i.e., the rate of pCR was
undesirable effects of metformin solely rely treated with the drug are estimated to be 24% in the metformin group, 8.0% in
the nonmetformin group, and 16% in Jiralerspong et al.41 retrospectively found the ability of standard clinical metformin
the nondiabetic group).41 In this regard, that the use of metformin in standard doses to efficiently lower circulating levels
it could be argued that the report by clinical doses was associated with clini- of insulin can be extrapolated to benefi-
Jiralerspong et al. provides evidence that cal benefit in diabetic patients (in whom cial effects in non-diabetic breast cancer
the use of metformin in standard clini- hyperinsulinemia-induced activation of patients. Moreover, it is just obvious that
cal doses may be associated with clinical signaling pathways downstream of the Jiralerspong et al.41 did not evaluate
benefit irrespective of metformin-induced insulin receptor in cancer cells could be the relevance of the AMPK/mTOR →
pro-angiogenic effects and/or metformin- significant). Therefore, on-going trials of IGF-IR feedback mechanism in the clini-
triggered mechanisms of acquired autore- metformin as an adjuvant treatment in cal efficacy of metformin (as it was not an
sistance.39 However, stated more neutrally, breast cancer should elucidate whether end-point of their study).
combination with conventional therapy, stem cells in preclinical models in vitro. cells) and trastuzumab with metformin
metformin co-treatment may provide a Alternatively, and given that: (a) breast (both targeting tumor-initiating cells) in
successful therapeutic strategy to prevent cancer patients with HER2 + disease who women diagnosed with HER2-positive
cancer recurrence and improve long-term experience a pCR to neoadjuvant che- primary breast cancer.53
survival (Fig. 2). Perhaps, the unexpected motherapy experience a better DFS with
ability of metformin treatment to attack long-term follow-up;50 (b) the HER2 Metformin and Breast Cancer: A
just the root of the dandelion may largely pathway plays an important role in the Hormetic Corollary
explain the ability of standard clini- maintenance of breast cancer stem cells;51
cal doses of metformin to significantly (c) stem cells of HER2-positive breast Even in the best-case molecular scenario
enhance the rate of pathological complete carcinomas express the highest HER2 for achieving metformin-related anti-
responses (pCR) in diabetic breast cancer levels and are sensitive to the anti-HER2 breast cancer clinical benefits, we should
patients receiving metformin and neo- monoclonal antibody trastuzumab,52 and acknowledge that, given the remarkably
adjuvant chemotherapy.41 To definitely (d) HER2-positive pre-clinical models heterogenicity of breast cancer disease,
test this hypothesis, disease-free survival are differentially sensitive to the anti- it seems likely that the characteristics of
(DFS) may be the best reflection (pri- tumor activity of metformin,11,12,23,24 cru- metformin-sensitive bulk proliferating
mary end point) of metformin activity cial evidence of the clinical efficacy of tumor cells and slow/non-dividing breast
against breast cancer stem cells—but this metformin can be obtained from small cancer-initiating stem cells may evolve
will require long studies and large patient “proof-of-principle” studies with neoad- under the selection pressure of chronic
numbers—with secondary end point juvant regimens including neoadjuvant metformin treatments. Recent work by
of serially measuring the breast cancer chemotherapy (to target bulk tumor Anisimov et al.54 in female SHR mice
has revealed that, unlike in cancer-prone sustain fitness of oncogenic transformed danger certainly merits to be examined in
transgenic mice carrying the HER2 onco- cells (Fig. 3).56 Administration of met- detail when moving ahead with planned
gene,11,12 metformin feeding—at concen- formin results in changes that closely par- chemopreventive, neoadjuvant and adju-
trations that approximately the clinical allel the metabolic and gene expression vant metformin-based breast cancer
situation—unexpectedly fails to decrease patterns of CR animals.10,57 Consequently, trials.
the incidence of malignant tumors includ- metformin mimicked CR can elicit a pro-
ing mammary carcinomas while extending tective survival response that promotes Acknowledgements
lifespan, thus suggesting some pleiotropic longevity and healthy aging. However, Alejandro Vazquez-Martin is the recipient
effects related to long-term treatments like DNA damage, hormetic responses of a “Sara Borrell” post-doctoral contract
with metformin. By acting as a caloric to metformin-induced metabolic stress (CD08/00283, Ministerio de Sanidad
restriction mimetic (CRM), it is expected could trigger also development of cancer y Consumo, Fondo de Investigación
that chronic administration of low levels depending on the amount, location and Sanitaria-FIS-, Spain). This work was sup-
of metformin can stimulate cell intrinsic the type of cell sustaining the damage.58 ported in part by Instituto de Salud Carlos
capacity for self-maintenance and repair Therefore, one cannot rule the possibil- III (Ministerio de Sanidad y Consumo,
(hormesis by definition),55 thus promot- ity that interfering with glucose/insulin Fondo de Investigación Sanitaria-FIS-,
ing beneficial anti-cancer/anti-aging metabolism in a normal adult on a normal Spain, Grants CP05-00090, PI06-0778
effects. However, metformin-induced diet will never be completely safe. The and RD06-0020-0028 to Javier A.
highly-adaptive “hormetic phenotypes” ability of metformin to trigger anticancer Menendez). Javier A. Menendez was also
(at the cellular level) can be positively responses by suppressing crucial metabolic supported by a Grant from the Fundación
selected with harmful consequences (at axis while concurrently boosting defenses Científica de la Asociación Española
the organismal level) if they efficiently that maintain cell integrity with hormesis Contra el Cáncer (AECC, Spain).