Statins and endocrine resistance in breast cancer

Abstract

Most breast cancers are hormone-receptor positive (HR + ). However, more women eventually die from HR + breast cancer than from either HER2 + or triple negative breast cancer. Endocrine therapies continue to be the mainstay of treatment. In 40% of these cases, recurrences in early-stage disease and progression in the metastatic setting are largely a function of the development of endocrine resistance. A multitude of mediators and pathways have been associated with endocrine resistance in breast cancer including the mevalonate pathway, which is integral to cholesterol biosynthesis. The mevalonate pathway and the downstream activation of associated cytoplasmic pathways including PI3K-AKT-mTOR and RAS-MEK-ERK have been known to affect cancer cell proliferation, cell survival, cell invasion, and metastasis. These are important mechanisms leading to the inevitable development of endocrine resistance in HR + breast cancer. Statins are a class of drugs that inhibits HMG-CoA reductase, an enzyme in the mevalonate pathway that plays a central role in cholesterol production. In vitro and in vitro studies suggest that the role of statins in blocking the mevalonate pathway effectively disrupts downstream pathways involved in estrogen receptor expression and cellular processes such as cell survival, proliferation, stress, cell cycle, inhibition of apoptosis, and autophagy. Overcoming these key mechanisms heralds a role for statins in the prevention of endocrine resistance.

Statins Aggravate the Risk of Insulin Resistance in Human Muscle

“…Active GTP-loaded Rab promotes GLUT4 translocation to the plasma membrane. Active AMPK can also mediate the emergence of more active GTP-loaded Rab [43,47,48]. The prenylation of small GTPases may be depleted over time via the inhibition of the mevalonate pathway and even by an increase in HMGCR expression, as we showed recently by Grunwald et al in 2020 under statin treatment [26].…”

“…However, this is different for muscle, which may switch to an alternative pathway for GLUT4 translocation [43]. Statins inhibit the formation of isoprenoids and thus farnesyl and geranylgeranyl pyrophosphates, from the mevalonate pathway and required for small GTPase prenylation, are reduced [43,47]. RabGTPases are hydrophobically prenylated by Rab geranylgeranyl transferase to bind to their target membrane structures, such as GLUT4 vesicles, and to direct the translocation of GLUT4 [48,49].…”

“…Muscle cryosection GLUT4 immunostaining was performed as previously described [47]. Briefly, after fixation and permeabilization, sections were stained with rabbit GLUT4 antiserum followed by incubation with biotin-conjugated Fab2 and streptavidin-Cy3 (Table 2).…”

The Present and Future of Clinical Management in Metastatic Breast Cancer

“…The output of this biological process is the generation of the 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR) that has been associated with cancer growth leading to poorer prognosis. [ 122 ] Hence, statins, the HMGCR inhibitors, are currently of increasing translational interest for inhibiting tumor growth and angiogenesis.…”

The Present and Future of Clinical Management in Metastatic Breast Cancer

“…Activation of the PIK3 leads to recruitment of the AKT kinase and subsequently intracellular cascade of phosphorylation of mTOR, a potent driver of cancer cell progression and survival [119]. PI3K mutation and AKT activation are also paramount in endocrine therapy resistance [120]. To this extent, several ongoing clinical trials are investigating the efficacy and safety of PI3K/AKT/mTOR inhibitors, in combination with estrogen therapy and standard-of-care chemotherapy.…”