Sara Zoghi

Background: Breast cancer is a heterogeneous disease concerning the transformation of mammary ductal and luminal epithelial cells.¹ It was the most diagnosed cancer of 2020, with ER+ cancers accounting for over 70% of the diagnoses.¹  Worldwide, it accounts for 15.5% of all female deaths, making it the most deadly cancer for women.³ Due to its heterogeneity, tumor classification is imperative in characterizing the cancer and determining the most appropriate treatment. It is most commonly classified into 5 molecular signatures: luminal A, luminal B, human epidermal growth factor receptor 2 positive (HER2+), basal, and normal-like.¹ For the purposes of this review, we will primarily be focusing on luminal A and B breast cancers, which are estrogen receptor positive (ER+) that are treated with hormone therapies.¹  Risk factors carry both genetic and environmental influences and include family history, race, ethnicity, diet, obesity, and hormonal exposure.³ For the scope of this review, we will narrow our focus to obesity, which is defined as having a BMI >30.⁴ About 13% of the world’s adult population is considered obese.⁴ This prevalence in obesity has a direct relationship with breast cancer by altering the tumor environment via leptin-mediated P53-HIF1ɑ/PKM2-aromatase pathway.²

Objectives: In this narrative review, I explored the mechanism in which obesity stimulates breast cancer proliferation through the p53-HIF1ɑ/PKM2-aromatase pathway.

Search Methods: A PubMed search was conducted using articles from 2018-2024 with the following keywords: “breast cancer and diet,” “breast cancer and obesity,” and “leptin and breast cancer.”

Results: Researchers found that leptin overproduction is induced by obesity and can potentiate breast cancer through regulation of P53-HIF1ɑ/PKM2-aromatase pathway.² Obesity is associated with increases in the adipokine leptin.² This peptide, in turn, stimulates expression of aromatase, the rate-limiting enzyme of estrogen synthesis.² A study found that leptin stimulates expression of Protein Kinase C (PKC), which then activates ERK1/2 signaling pathway.² ERK1/2 also inhibits p53, a tumor suppressor.² Suppression of p53 allows for activation of pro-aromatase factors.² Downstream of ERK1/2, HIF1ɑ, and PKM2 are Hsp90 client proteins that regulate aromatase expression.² In vitro studies using adipose stromal cells (ASCs) from human mammary tissues confirmed the role of PKC and ERK1/2 in the aromatase pathway.² Upon introduction of PKC and MEK1/2 inhibitors, there was a dose-dependent decrease in aromatase activity.² In vivo studies using ovariectomized female mice further investigated the effects of diet on tumor metastasis. Using hormone-sensitive murine breast cancer cell lines, researchers found metastasis to the lungs was significantly higher in the HFD group.² Taken together, these findings implicate how obesity can alter breast cancer progression.

Conclusion: Obesity plays a role in breast cancer by upregulating leptin, an adipokine involved in estrogen synthesis. Increases in estrogen stores can feed certain types of breast cancer and promote their growth.⁵ PKC and ERK1/2 are mediators of the aromatase pathway and work via activation by leptin. ERK1/2 also works to inhibit p53, a tumor suppressor. These findings can be extrapolated to promote therapies that can target the mediators of the aromatase pathway and combat resistance.⁵

Works Cited:

1. Clusan L, Ferrière F, Flouriot G, Pakdel F. A Basic Review on Estrogen Receptor Signaling Pathways in Breast Cancer. Int J Mol Sci. 2023;24(7):6834. Published 2023
2. Zahid H, Subbaramaiah K, Iyengar NM, et al. Leptin regulation of the p53-HIF1α/PKM2-aromatase axis in breast adipose stromal cells: a novel mechanism for the obesity-breast cancer link. Int J Obes (Lond). 2018;42(4):711-720. doi:10.1038/ijo.2017.273
3. Coughlin SS. Epidemiology of Breast Cancer in Women. Adv Exp Med Biol. 2019;1152:9-29. doi:10.1007/978-3-030-20301-6_2
4. García-Estévez L, Cortés J, Pérez S, Calvo I, Gallegos I, Moreno-Bueno G. Obesity and Breast Cancer: A Paradoxical and Controversial Relationship Influenced by Menopausal Status. Front Oncol. 2021;11:705911. Published 2021 Aug 13. doi:10.3389/fonc.2021.705911
5. Kharb R, Haider K, Neha K, Yar MS. Aromatase inhibitors: Role in postmenopausal breast cancer. Arch Pharm (Weinheim). 2020;353(8):e2000081. doi:10.1002/ardp.202000081