Accelerated geroncogenesis in hereditary breast-ovarian cancer syndrome

Abstract

The geroncogenesis hypothesis postulates that the decline in metabolic cellular health that occurs naturally with aging drives a "field effect" predisposing normal tissues for cancer development. We propose that mutations in the cancer susceptibility genes BRCA1/2 might trigger "accelerated geroncogenesis" in breast and ovarian epithelia. By speeding up the rate at which the metabolic threshold becomes "permissive" with survival and expansion of genomically unstable pre-tumoral epithelial cells, BRCA haploinsufficiency-driven metabolic reprogramming would operate as a bona fide oncogenic event enabling malignant transformation and tumor formation in BRCA carriers. The metabolic facet of BRCA1 one-hit might involve tissue-specific alterations in acetyl-CoA, α-ketoglutarate, NAD+, FAD, or S-adenosylmethionine, critical factors for de/methylation or de/acetylation dynamics in the nuclear epigenome. This in turn might induce faulty epigenetic reprogramming at the "install phase" that directs cell-specific differentiation of breast/ovarian epithelial cells, which can ultimately determine the penetrance of BRCA defects during developmental windows of susceptibility. This model offers a framework to study whether metabolic drugs that prevent or revert metabolic reprogramming induced by BRCA haploinsufficiency might displace the "geroncogenic risk" of BRCA carriers to the age typical for those without the mutation. The identification of the key nodes that directly communicate changes in cellular metabolism to the chromatin in BRCA haploinsufficient cells may allow the epigenetic targeting of genomic instability using exclusively metabolic means. The validation of accelerated geroncogenesis as an inherited "one-hit" metabolic "field effect" might offer new strategies to therapeutically revisit the apparently irreversible genetic-hereditary fate of women with hereditary breast-ovarian cancer syndrome.

Keywords: BRCA1; Gerotarget; cancer; geroncogenesis; metabolism; metformin.

Figure 1. Hits and tumor formation in hereditary and nonhereditary carcinomas

The mechanisms that underline genetic predisposition to cancer were originally clarified by Knudson, who hypothesized that germline mutations occur in one allele of a tumor suppressor gene followed by somatic inactivation, or loss of function, of the remaining normal allele through mutations, deletions, or epigenetic repression (defined as loss of heterozygosity [LOH]) [15] (model 1). The Knudson “two-hit” hypothesis has been largely validated in most forms of autosomal hereditable cancer and has been also extended to sporadic forms of cancer, albeit at a greater level of complexity [84]. Because in the nonhereditary scenario, the first somatic mutation might be expected to occur at a rate approximately equal to that of the second mutation in the hereditary cases, a “one-hit” clone is a precursor to the tumor formation in nonhereditary forms of cancer (model 2), whereas all cells are “one-hit” clones in hereditary cancer syndromes. BRCA1-driven HBOC syndrome, however, apparently contradicts the original “two-hit” theory conformed by other familial cancer syndromes, in which consecutive deletion of two alleles accelerates tumorigenesis. Cancer predisposition upon inactivation of a single BRCA allele relates to the so-called haploinsufficiency phenomenon associated with heterozygosity, which results in genomic instability in breast/ovarian epithelial cells. This in turn may promote additional genetic changes in BRCA heterozygous cells, including the acquisition of new mutations that will precede and be permissive with the loss of BRCA (e.g., p53, ATM and CHK2) (model 3). The requirement of this “extra-hit”, although incongruous from the viewpoint of familial tumorigenesis mediated by tumor suppressor genes such as BRCA1 and BRCA2, appears to enable cancer-prone BRCA “one-hit” cells to evade the cell death processes that would otherwise occur upon loss of the remaining wild-type allele. Based on these models, cancer metabolic reprogramming is not the cause but rather the consequence of the mutations that originally generated malignancy and tumor growth (modified from original drawing published by Lindsay et al. [19]).

Figure 2. The “geroncogenic” hypothesis of carcinogenesis

The natural deterioration in the function of cellular metabolism that occurs with age can be sufficient to generate an aberrant metabolic state in normal tissues capable of facilitating the independent or subsequent acquisition of cancer-driving genetic alterations (modified from original drawing published by Lindsay et al. [19]). While the model predicts that the geroncogenic risk could increase with excessive calorie intake and/or a sedentary lifestyle, it also suggests the possibility of countering this risk with low-calorie diets, physical exercise and by gerosuppressant agents such as metformin, rapamycin, and plant-derived polyphenols including resveratrol [85-87].

Figure 3. BRCA1 haploinsufficiency induces “accelerated geroncogenesis”

Women carrying mutations in the cancer susceptibility genes BRCA1 and BRCA2 might undergo a tissue- and cell type-specific process of “accelerated geroncogenesis” in breast and ovarian epithelia. BRCA1 haploinsufficiency-driven metabolic rewiring of breast/ovarian epithelial cells to metabolic portraits capable of supporting the high bioenergetic and biosynthetic requirements of genomically unstable breast/ovarian epithelial cells to progress to a fully malignant phenotype might constitute an unanticipated and inherited form of metabolic reprogramming linked to increased risk of oncogenesis (modified from original drawing published by Lindsay et al. [19]). In this model of “accelerated geroncogenesis”, there would be a reduction in the time required for breast and ovarian epithelial cells to phenocopy a cancer-like metabolism, thus accelerating the rate at which the metabolic threshold becomes “permissive” with the survival and expansion of the pre-tumoral “one-hit” BRCA-deficient breast/ovarian epithelial cells. Although BRCA haploinsufficiency per se would significantly increase the “geroncogenic” risk, it would also make these patients more responsive to preventative and therapeutic strategies based on new drugs or approaches aimed to halt the aberrant metabolic reprogramming of breast/ovarian epithelial cells.

Box. OCR: Oxygen Consumption Rates, in pMoles O²/min

ECAR: Extracellular Acidification Rate, in mpH/min. ECAR data were not artificially altered by changes in pH values, as in fact closely paralleled changes in PPR (normalized Proton Production Rate, in nmol H+/min) values (data not shown)

Figure 4. Metabolic regulation of epigenetics: The reprogramming dimension of BRCA1-driven accelerated geroncogenesis

Haploinsufficiency for BRCA1/2 can lead to cell-type-specific mitochondrial functioning that invokes a significantly altered mitochondria-to-nucleus retrograde response in breast/ovarian epithelia. This response may induce relevant changes to the nuclear epigenome via alteration of key metabolic co-factors closely associated with the processes of active de/methylation or de/acetylation (e.g., acetyl-CoA, α-ketoglutarate [α-KG], NAD⁺, FAD, and S-adenosylmethionine [SAM]), which might increase the penetrance of tumor susceptibility, but may also illuminate new interventions that can reverse the epigenetic effects of metabolic reprogramming to decrease cancer risk associated with germline alterations in BRCA1/2 tumor suppressor genes.