Total long-chain polyunsaturated n-3 fatty acids level is an independent predictive factor of breast cancer multifocality in women with positive hormone-receptors tumors.

In a previous pilot study, we showed that polyunsaturated n-3 fatty acids of breast adipose tissues were associated with breast cancer multifocality. In the present study, we investigated biochemical, clinical and histological factors associated with breast cancer focality in a large cohort of women with positive hormone-receptors tumors. One hundred sixty-one consecutive women presenting with positive hormone-receptors breast cancer underwent breast-imaging procedures including a Magnetic Resonance Imaging prior to treatment. Breast adipose tissue specimens were collected during surgery of tumors. A biochemical profile of breast adipose tissue fatty acids was established by gas chromatography. Clinicopathologic characteristics were correlated with multifocality. We assessed whether these factors were predictive of breast cancer focality. We found that tumor size (OR = 1.06 95%CI [1.02-1.09], p < 0.001) and decreased levels in breast adipose tissue of long-chain polyunsaturated n-3 fatty acids (OR = 0.11 95%CI [0.01-0.98], p = 0.03), were independent predictive factors of multifocality. Low levels of long chain polyunsaturated n-3 fatty acids in breast adipose tissue appear to contribute to breast cancer multifocality. The present results reinforce the link between dietary habits and breast cancer clinical presentation.

Low Levels of Omega-3 Long-Chain Polyunsaturated Fatty Acids Are Associated with Bone Metastasis Formation in Premenopausal Women with Breast Cancer: A Retrospective Study.

In the present study, we investigated various biochemical, clinical, and histological factors associated with bone metastases in a large cohort of pre- and postmenopausal women with breast cancer. Two hundred and sixty-one consecutive women with breast cancer were included in this study. Breast adipose tissue specimens were collected during surgery. After having established the fatty acid profile of breast adipose tissue by gas chromatography, we determined whether there were differences associated with the occurrence of bone metastases in these patients. Regarding the clinical and histological criteria, a majority of the patients with bone metastases (around 70%) had tumors with a luminal phenotype and 59% of them showed axillary lymph node involvement. Moreover, we found a negative association between the levels of n-3 long-chain polyunsaturated fatty acids (LC-PUFA) in breast adipose tissue and the development of bone metastases in premenopausal women. No significant association was observed in postmenopausal women. In addition to a luminal phenotype and axillary lymph node involvement, low levels of n-3 LC-PUFA in breast adipose tissue may constitute a risk factor that contributes to breast cancer bone metastases formation in premenopausal women.

Increased BRCA1 protein in mammary tumours of rats fed marine omega-3 fatty acids.

Any factor affecting BRCA gene regulation may be of interest in the prevention of breast tumourigenesis. We studied the influence of dietary docosahexaenoic acid (DHA), a major omega-3 fatty acid present in marine products, on rat autochthonous mammary tumourigenesis. DHA-supplementation significantly reduced the incidence of tumours (30%, P=0.007) and led to a 60% increase (P=0.02) in BRCA1 protein level. Since DHA influences the product of a major tumour suppressor gene, this finding may contribute to the observation that high-fish consumption reduces the risk of breast cancer.

Dietary beta-carotene inhibits mammary carcinogenesis in rats depending on dietary alpha-linolenic acid content.

To investigate whether dietary alpha-linolenic acid (ALA) content alters the effect of beta-carotene on mammary carcinogenesis, we conducted a chemically induced mammary tumorigenesis experiment in rats randomly assigned to four nutritional groups (15 rats per group) varying in beta-carotene supplementation and ALA content. Two oil formula-enriched diets (15 %) were used: one with 6 g ALA/kg diet in an essential fatty acids (EFA) ratio of linoleic acid:ALA of 5:1 w/w (EFA 5 diet), the other with 24 g ALA/kg diet in an EFA ratio of 1:1 w/w (EFA 1 diet), both designed with a similar linoleic acid content. beta-Carotene was either added (10 mg/kg diet per d) or not added to these diets. beta-Carotene supplementation led to decreased tumour incidence and tumour growth when added to the EFA 5 diet, whereas it had no effect when added to the EFA 1 diet. The decreased tumour growth did not result from an involvement of lipoperoxidation (tumour malondialdehyde content being similar between the groups) or from an inhibition of tumour cell proliferation (as there was an unchanged S phase fraction in the tumours). We concluded that an adequate content of ALA in the diet is required to allow a protective effect of beta-carotene in mammary carcinogenesis. Whether such an interaction between ALA and beta-carotene influences the risk of breast cancer in women needs to be investigated.

CDK1-cyclin B1 mediates the inhibition of proliferation induced by omega-3 fatty acids in MDA-MB-231 breast cancer cells.

Long-chain omega-3 polyunsaturated fatty acids are thought to inhibit the development of breast cancer. We investigated the effects of docosahexaenoic and eicosapentaenoic acids on the proliferation of MDA-MB-231 human mammary epithelial cells. Both docosahexaenoic and eicosapentaenoic acids decreased cell growth with a higher efficiency for docosahexaenoic acid (87% at 100 microM versus 74% for eicosapentaenoic acid). The effect on specific cell cycle phases was studied. G2/M duration was markedly increased by docosahexaenoic and by eicosapentaenoic acids (respectively by more than seven- and six-fold at 50 microM) when cells were synchronized at the G1/S boundary and released in the cell cycle. In contrast, there was no alteration of G1 or S phases. The expression of cyclin A, cyclin B1 and cyclin-dependent kinase 1, the regulators required for the progression from G2 to mitosis, were all decreased by these fatty acids (western blot). Since omega-3 fatty acids had no effect on the S phase, thus ruling out an involvement of cyclin A in their anti-proliferative effect, we examined whether the regulation of the cyclin-dependent kinase 1-cyclin B1 complex was altered. Upon omega-3 fatty acids treatment, cyclin B1 phosphorylation was inhibited and the expression of the cell division cycle 25C phosphatase, which dephosphorylates cyclin-dependent kinase 1, was decreased. We conclude that the anti-proliferative effect of omega-3 fatty acids occurs via the regulation of the cyclin-dependent kinase 1-cyclin B1 complex.

N-3 and N-6 fatty acids in breast adipose tissue and relative risk of breast cancer in a case-control study in Tours, France.

Experimental studies have indicated that n-3 fatty acids, including alpha-linolenic acid (18:3 n-3) and long-chain n-3 polyunsaturated fatty acids inhibit mammary tumor growth and metastasis. Earlier epidemiological studies have given inconclusive results about a potential protective effect of dietary n-3 polyunsaturated fatty acids on breast cancer risk, possibly because of methodological issues inherent to nutritional epidemiology. To evaluate the hypothesis that n-3 fatty acids protect against breast cancer, we examined the fatty acid composition in adipose tissue from 241 patients with invasive, nonmetastatic breast carcinoma and from 88 patients with benign breast disease, in a case-control study in Tours, central France. Fatty acid composition in breast adipose tissue was used as a qualitative biomarker of past dietary intake of fatty acids. Biopsies of adipose tissue were obtained at the time of surgery. Individual fatty acids were measured as a percentage of total fatty acids, using capillary gas chromatography. Unconditional logistic regression modeling was used to obtain odds ratio estimates while adjusting for age, height, menopausal status and body mass index. We found inverse associations between breast cancer-risk and n-3 fatty acid levels in breast adipose tissue. Women in the highest tertile of alpha-linolenic acid (18:3 n-3) had an odds ratio of 0.39 (95% confidence intervals [CI] = 0.19-0.78) compared to women in the lowest tertile (trend p = 0.01). In a similar way, women in the highest tertile of docosahexaenoic acid (22:6 n-3) had an odds ratio of 0.31 (95% CI = 0.13-0.75) compared to women in the lowest tertile (trend p = 0.016). Women in the highest tertile of the long-chain n-3/total n-6 ratio had an odds ratio of 0.33 (95% confidence interval = 0.17-0.66) compared to women in the lowest tertile (trend p = 0.0002). In conclusion, our data based on fatty acids levels in breast adipose tissue suggest a protective effect of n-3 fatty acids on breast cancer risk and support the hypothesis that the balance between n-3 and n-6 fatty acids plays a role in breast cancer.