Increased expression of fatty acid synthase and progesterone receptor in early steps of human mammary carcinogenesis

Esslimani-Sahla, Majida; Thézenas, Simon; Simony-Lafontaine, Joëlle; Kramar, Andrew; Lavaill, Roselyne; Chalbos, Dany; Rochefort, Henri

doi:10.1002/ijc.22202

Cited by 45 publications

(29 citation statements)

References 32 publications

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“…Their findings are comparable to ours, though this group did not describe the suprabasal cell staining seen in the current study. The authors 19 suggest that these findings are most likely in keeping with epithelial stem cells because of the topographic location. These results provide endorsement for the proposal by some that FASN expression may reflect increased membrane synthesis and cell growth, as supported by studies of the gastrointestinal tract, brain and genitourinary system.…”

Section: Discussionmentioning

confidence: 90%

“…Double-staining experiments indicate that FASN-positive cells do not exhibit a characteristic 'basal' (cytokeratin 5/6-positive) or myoepithelial (p63-positive) immunophenotype. Esslimani-Sahla et al 19 have also described FASN immunoreactivity through a monoclonal FASN antibody as a scattered expression pattern in normal and pathological structures of epithelial mammary cells. Their findings are comparable to ours, though this group did not describe the suprabasal cell staining seen in the current study.…”

Section: Discussionmentioning

confidence: 99%

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Characterization of a novel anti-fatty acid synthase (FASN) antiserum in breast tissue

et al. 2008

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Fatty acid synthase (FASN) expression has been reported in many different tumors, including breast cancer. In gene microarray studies, the fatty acid synthase gene co-clustered with cytokeratins 5 and 17 and other genes that defined the basal-like subset of breast cancers. To define the use of this marker in breast pathology, a rabbit polyclonal antiserum (S143) to a peptide fragment of this gene was produced and compared with a commercially available monoclonal antibody by immunohistochemistry on various tissue microarrays and whole tissue sections. The tissue microarrays included 1090 breast cancers and 244 normal breast tissues. Whole tissue sections consisted of benign and malignant tissues from breast resection specimens. In contrast to other 'basal' markers identified by gene expression profiling data, the fatty acid synthase (FASN) expression pattern in normal breast was notable for its expression in only a small subset of basal and suprabasal cells. Dual staining experiments revealed that the subpopulation of cells labeling with FASN did not coexpress myoepithelial markers CK5/6 or p63, but did coexpress e-cadherin. In addition to staining a subset of basal and suprabasal cells, the antiserum highlighted apocrine differentiation, and stained 106/144 (74%) cases of columnar cell lesions and five of five cases of flat epithelial atypia. Despite its association with basal keratins in gene array studies, FASN expression did not correlate significantly with the outcome in breast cancer. We describe an expression pattern that highlights only a subset of basal and suprabasal cells in normal breast ducts and we show by dual expression studies that this subset of cells is different from myoepithelial and basal cytokeratin-positive cells. In addition, FASN expression is described in apocrine metaplasia, columnar cell lesions, and flat epithelial atypia.

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Characterization of a novel anti-fatty acid synthase (FASN) antiserum in breast tissue

et al. 2008

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“…By immunohistochemistry, in studying the early stages of breast carcinogenesis, we detected a statistically significant increased level of PR and FASN level in proliferating breast lesions in comparison to adjacent normal tissues [52] (Fig. 3).…”

Section: Prs In Breast Cancermentioning

confidence: 89%

“…Accordingly, we found that FASN and HER2/ Neu upregulation were strongly correlated in high-grade DCIS [52] as it is in the HER 2/Neu invasive breast cancers [54]. Other mechanisms than increased PR level can facilitate progesterone activity, such as gene amplification of the co-activator AIB1 [55], an unbalance in breast cancer between the two PR isoforms A and B [56], or a decreased level of a competitor.…”

Section: Prs In Breast Cancermentioning

confidence: 99%

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The Role of Sex Steroid Receptors on Lipogenesis in Breast and Prostate Carcinogenesis: A Viewpoint

Rochefort

Chalbos

2010

HORM CANC

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Cancer cells require both nutrients and mitogens to multiply and survive in the unfavorable microenvironment of solid tumors or metastases before angiogenesis. Most cancer cells do not use fatty acids (FA) from the circulation but synthesize them in situ especially to make membranes and lipid signals required for continuously dividing cells. Three lipogenic enzymes are overexpressed, induced by sex steroid hormones and responsible for the in situ increased lipogenesis in cancer cells. We propose that in the early stages of human breast and prostate carcinogenesis, an increased activity of sex steroid receptors is partly responsible for the overexpression of FA synthase (FASN) whose regulation in cancer cells has been particularly studied. Increased activity of androgen receptor (AR), via different mechanisms, was extensively reported in prostate cancer. An increased level/and or activity of progesterone receptors, correlated with an increased expression of FASN, was found both in early stages of breast carcinogenesis and during the hormone replacement therapy of menopausal women. While the majority of recent targeted therapies are based on inhibition of mitogenic pathways, the inhibition of cancer cell nutrition by interfering with lipid synthesis and hormone action should open the way to new therapeutic and preventive approaches of hormonedependent cancers.

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BRCA1 and acetyl‐CoA carboxylase: The metabolic syndrome of breast cancer

Brunet

Vázquez-Martín

Colomer

et al. 2007

Molecular Carcinogenesis

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Breast cancer-associated mutations affecting the highly-conserved C-terminal BRCT domains of the tumor suppressor gene breast cancer susceptibility gene 1 (BRCA1) fully disrupt the ability of BRCA1 to interact with acetyl coenzyme A carboxylase alpha (ACCA), the rate-limiting enzyme catalyzing de novo fatty acid biogenesis. Specifically, BRCA1 interacts solely with the phosphorylated (inactive) form of ACCA (P-ACCA), and the formation of the BRCA1/P-ACCA complex interferes with ACCA activity by preventing P-ACCA dephosphorylation. One of the hallmarks of aggressive cancer cells is a high rate of energy-consuming anabolic processes driving the synthesis of lipids, proteins, and DNA (all of which are regulated by the energy status of the cell). The ability of BRCA1 to stabilize the phosphorylated/inactive form of ACCA strongly suggests that the tumor suppressive function of BRCA1 closely depends on its ability to mimic a cellular-low-energy status, which is known to block tumor cell anabolism and suppress the malignant phenotype. Interestingly, physical exercise and lack of obesity in adolescence have been associated with significantly delayed breast cancer onset for Ashkenazi Jewish women carrying BRCA1 gene mutations. Further clinical work may explore a chemopreventative role of "low-energy-mimickers" deactivating the ACCA-driven "lipogenic phenotype" in women with inherited mutations in BRCA1. This goal might be obtained with current therapeutic approaches useful in treating the metabolic syndrome and associated disorders in humans (e.g., type 2 diabetes and obesity), including metformin, thiazolidinediones (TZDs), calorie deprivation, and exercise. Alternatively, new forthcoming ACCA inhibitors may be relevant in the management of BRCA1-dependent breast cancer susceptibility and development.

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Increased expression of fatty acid synthase and progesterone receptor in early steps of human mammary carcinogenesis

Cited by 45 publications

References 32 publications

Characterization of a novel anti-fatty acid synthase (FASN) antiserum in breast tissue

Characterization of a novel anti-fatty acid synthase (FASN) antiserum in breast tissue

The Role of Sex Steroid Receptors on Lipogenesis in Breast and Prostate Carcinogenesis: A Viewpoint

BRCA1 and acetyl‐CoA carboxylase: The metabolic syndrome of breast cancer

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