Oral Presentation Annual Meetings of the Endocrine Society of Australia and Society for Reproductive Biology and Australia and New Zealand Bone and Mineral Society 2016

Obesity is associated with an increase in the HIF1α-PKM2-Aromatase Axis in Breast Adipose Stromal Cells that is reversed by caloric restriction: implications for obesity-related breast cancer (#40)

Heba Zahid 1 2 , Neil M Iyengar 3 4 , Xi Kathy Zhou 3 , I-Chun Chen 5 , Priya Bhardwaj 5 , Ayca Gucalp 4 , Monica Morrow 6 , Clifford A Hudis 4 5 , Andrew J Dannenberg 5 , Kristy A Brown 1 7
  1. Hudson Institute of Medical Research, Clayton, VIC, Australia
  2. Faculty of Applied Medical Science, Taibah University, Medina, Saudi Arabia
  3. Department of Healthcare Policy and Research, Weill Cornell Medical College, New York, USA
  4. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA
  5. Department of Medicine, Weill Cornell Medical College, New York, USA
  6. Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, USA
  7. Department of Physiology, Monash University, Clayton, Victoria, Australia

Obesity is a risk factor for estrogen receptor positive (ER+) postmenopausal breast cancer. In the breast, the main site of expression of aromatase, the rate-limiting enzyme in estrogen biosynthesis, is the adipose stromal cell (ASC). We have shown that hypoxia-inducible factor-1α (HIF1α) stimulates the expression of aromatase in breast ASCs in culture and more recently, HIF1α has been shown to act cooperatively with metabolic regulator pyruvate kinase M2 (PKM2) to stimulate aromatase expression. The current study aimed to determine whether these findings are relevant to obesity-associated breast cancer and whether caloric restriction (CR) leads to inhibition of the HIF1α/PKM2-aromatase axis.

Breast tissue was obtained following mastectomy (uninvolved quadrants; n=43). The expression of HIF1α, PKM2 and aromatase was measured by immunofluorescence and confocal imaging. ASC-specific staining was quantified using Metamorph® software. The same endpoints were measured in the mammary glands of diet-induced obese mice (n=8/group), ovariectomized at 4 wks and either fed a 10% low-fat diet (LFD) or 60% high-fat diet (HFD) for 10 wks. Mice then either continued on their respective diets or received 10%, 20% or 30% CR for 7 wks.

Body mass index (BMI) was correlated with increased expression of HIF1α, PKM2, and aromatase in human breast tissue, the expression of these factors being correlated with each other (p<0.0001). Staining intensity for PKM2, HIF-1α and aromatase was higher in mammary ASCs of mice fed a HFD compared to a LFD, and CR caused a decrease in the expression of these markers (p≤0.05).

Obesity is associated with an increase in the HIF1α/PKM2-aromatase axis in breast ASCs, an effect that is reversed by CR. Our findings thus provide new insights into the mechanisms by which obesity can promote breast cancer and support further study of CR to reduce breast cancer risk by inhibiting the HIF1α/PKM2-aromatase axis.