Abstract 4501: Mammary adipocytes mediate cytokine production and malignant progression of ER-positive breast cancer through NF-kB activation
Authors: Ruiz Manuel Picon , Tarifa Cynthia Morata , Qureshi Rehana , Yoon Hyunho , Shin Miyoung , Kurani Hetakshi , Slingerland Joyce M. 
Published: August 2018

Obesity increases the adverse prognosis of all breast cancer subtypes at any age, and is also associated with an increased risk of developing estrogen receptor-positive (ER+) breast cancers after menopause. However, mechanisms thereof are not fully known. We have identified one mechanism whereby obesity contributes to tumor progression. Cancers contain a subset of self-renewing stem cells that mediate treatment resistance and metastasis. We showed prolonged co-culture of in vitro differentiated adipocytes together with breast cancer lines or cultured primary dissociated human breast cancer cells increases secretion of pro-inflammatory cytokines IL6, IL8, CCL2, CCL5 and IP10. Prolonged exposure to these fat cells or to each cytokine increased the proportion of both ER+ and ER- breast cancer cells that form mammospheres and express ALDH1 activity in vitro and that can initiate primary tumors and metastasis in vivo. Differentiated adipocyte or cytokine exposures activate Src, and Src family kinase activity induced Sox2, cMyc and Nanog upregulation and miR302b induction. miR302b upregulation is Sox2-dependent, promotes cytokine-driven sphere formation, and in turn, stimulates cMYC and SOX2 expression. Finally Src was not only activated by differentiated adipocyte or cytokine exposures, it was also required to sustain cytokine induction, since Src inhibitors decreased cytokine production after co-culture. Thus, cancer cell invasion into local fat would establish feed-forward loops to activate Src, maintain pro-inflammatory cytokine production and increase tumor initiating cell abundance, tumor growth and metastasis.

It is well known that obesity mediates a chronic inflammatory state through NF-κB pathway driven pro-inflammatory cytokine expression. Our ongoing work investigates the role of NF-kB pathway in the inflammatory tumor promoting effects of obesity. We have observed that cytokine induction in breast cancer cell exposed to isolated mammary breast adipocytes is estrogen:ER dependent, since this effect in ER+ breast cancer cell is much greater than that in ER- cancer cells; and since the aromatase inhibitor, letrozole, reduced co-culture induced cytokine induction. We found NF-kB inhibitors prevent co-culture mediated cytokine induction, and that adipocyte co-culture increased RelA (p65) levels and its nuclear localization. Following invasion into local obese fat, high aromatase levels would increase local estrogen to drive cytokine induction upon mature adipocyte:cancer contact, and increase ER+ cancer stem cells and metastasis.

Citation Format: Manuel Picon Ruiz, Cynthia Morata Tarifa, Rehana Qureshi, Hyunho Yoon, Miyoung Shin, Hetakshi Kurani, Joyce M. Slingerland. Mammary adipocytes mediate cytokine production and malignant progression of ER-positive breast cancer through NF-kB activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4501.