Epidemiological and clinical studies indicate that obesity is associated with a worse postmenopausal breast cancer prognosis and an increased risk of endocrine therapy resistance. However, the mechanisms mediating these effects remain poorly understood. Here we investigate the molecular pathways by which obesity-associated circulating factors in the blood enhance estrogen receptor alpha (ERalpha) positive breast cancer cell viability and growth.

Blood serum was collected from postmenopausal breast cancer patients and pooled by body mass index (BMI) category (Control: 18.5-24.9 kg/m2; Obese: [greater than or equal to] 30.0 kg/m2). The effects of patient sera on MCF-7 and T47D breast cancer cell viability and growth were examined by MTT and colony formation assays, respectively. Insulin-like growth factor receptor 1(IGF-1R), Akt, and ERK1/2 activation and genomic ER activity were assessed to determine their possible contribution to obese patient sera-induced cell viability and growth. To further define the relative contribution of these signaling pathways, cells grown in patient sera were treated with various combinations of ER, PI3K/Akt, and MAPK targeted therapies. Comparisons between cells exposed to different experimental conditions were made using one-way ANOVA and Student's t test.

Cells grown in media supplemented with obese patient sera displayed greater cell viability and growth as well as IGF-1R, Akt, and ERK1/2 activation relative to control sera. Despite the lack of a significant difference in genomic ER activity following growth in obese versus control patient sera, we observed a dramatic reduction in cell viability and growth after concurrent inhibition of the ERand PI3K/Akt signaling pathways. Further, we demonstrated that ER inhibition was sufficient to attenuate obese serum-induced Akt and ERK1/2 activation. Together, this data suggests that obesity promotes greater ER positive breast cancer cell viability and growth through enhanced crosstalk between nongenomic ER signaling and the PI3K/Akt and MAPK pathways.

Circulating factors in the serum of obese postmenopausal women stimulate ER positive breast cancer cell viability and growth by facilitating non-genomic ERcrosstalk with the PI3K/Akt and MAPK signaling pathways. These findings provide valuable insight into one mechanism by which obesity may promote ER positive postmenopausal breast cancer progression and endocrine therapy resistance.