Abstract P6-11-07: Role of insulin resistance in HR+ mammary carcinogenesis

Abstract Hormone receptor (HR+) breast cancer (BC) is responsible for more than 80% BC cases and more than 60% BC-related deaths in the US. The incidence and severity of BC are influenced by a variety of modifiable risk factors, including (but not limited to) nutritional behaviors and obesity. Specifically, women with a body mass index (BMI) > 25 Kg/m2 exhibit an approx. 1.4-fold increase in the risk of developing postmenopausal HR+ BC as compared to women with BMI < 25 Kg/m2. Along similar lines, women with type 2 diabetes (T2D) – one of many consequences of obesity – are at 1.23-fold increased risk to develop postmenopausal HR+ BC as compared to women without T2D. Moreover, a BMI >30 Kg/m2 has been associated with decreased progression-free survival and overall survival (OS) in women with HR+ BC. Thus, a high number of postmenopausal HR+ BC cases and BC-related deaths could be effectively avoided by modifying dietary habits, both in prophylactic and therapeutic settings. Mechanistically, obesity provokes numerous alterations that have been linked to accrued postmenopausal HR+ carcinogenesis, encompassing (1) increased circulating levels of glucose and insulin – reflecting insulin resistance (IR) coupled to T2D, (2) increased levels of estrogen, produced locally and systematically by adipocytes, and (3) chronic inflammation of the breast adipose tissue (AT). However, the relative contribution of IR vs. other obesity-associated alterations to BC development and sensitivity to treatment has not been elucidated. At least in part, this reflects the two most common approaches employed to cause obesity in preclinical studies: the use of high-fat diets (HFDs) and/or mice genetically predisposed to develop obesity (e.g., ob/ob mice), neither of which is suitable to uncouple IR from all other metabolic, hormonal, and inflammatory effects of obesity. Here, we combined a unique model of HR+HER2- carcinogenesis that recapitulates key immunobiological features of human HR+ BC (notably, a cold tumor microenvironment coupled to a scarce sensitivity to immunotherapy, and exquisite sensitivity to CDK4/6 inhibitors), as established in mice by medroxyprogesterone acetate (M) pellets combined with 7,12-dimethylbenz[a]anthracene (D) oral administration, with a novel model of pure IR originating from the AT-specific deletion of RAB10, member RAS oncogene family (Rab10), a transducer of insulin signaling in adipocytes. Importantly, these mice are neither hyperphagic nor overweight, have normal glucose level at baseline and do not exhibit inflammatory alterations in the AT, but nonetheless display IR. While a HFD shortens tumor-free survival (TFS) in immunocompetent mice subjected to M/D-driven oncogenesis, it does not alter the growth of detectable M/D-driven tumors. Conversely, IR as imposed by the loss of Rab10 in the AT failed to alter TFS but accelerated the growth of tumors, resulting in shortened OS. Moreover, the deletion of Rab10 from the mouse AT enabled the development of tumors displaying features of increased aggressiveness, including systematic loss of progesterone receptor (PR) expression. Finally, the growth of tumors emerging in in the context of a Rab10/- AT could be efficiently controlled by the systemic administration of metformin. In line with this notion, orthotopically injected mouse triple negative BC AT-3 cells grew faster in mice bearing an AT-specific deletion of Rab10 as compared to their wild-type littermates. In conclusion, IR as imposed by the loss of Rab10 in the mouse AT converts HR+ mammary carcinomas as driven by M/D into HR- lesions with increased aggressiveness. These findings have major implications for ethnic groups that are at high risk for T2D at BMIs that are considered normal for Caucasians, such as women of African American and Asian descent, especially in view of the fact that women from these ethnic groups are known to be at increased risk for aggressive triple-negative BC as compared to their Caucasian counterparts. Citation Format: Aitziber Buque, Maria Belen Picatoste, Norma Bloy, Lucie Yammine, Rosemary Leahey, Ai Sato, Emma Johnson, Timothy E. McGraw, Lorenzo Galluzzi. Role of insulin resistance in HR+ mammary carcinogenesis [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-11-07.