Therapeutics targeting the metastatic breast cancer bone microenvironment.

Breast cancer (BC) patient prognosis has improved over the past 2 decades with a 99% 5-year survival rate for localized BC, yet metastatic breast cancer (mBC) continues to cause high mortality with a 5-year survival rate of 29%. Approximately 70% of BC metastases occur in the bone, with estrogen receptor (ER) positive BC exhibiting a particular affinity to bone. Once BC metastasizes to the bone, curative treatments are not available, thus therapeutic approaches are focused on palliative care and prevention of skeletal related events while attempting to slow metastatic progression. Recent advances in molecularly targeted agents have enhanced the repertoire of options for mBC patients, but immunotherapies have not yet been fully translated to ER+ tumors. Thus mBC patients have yet to fully benefit from novel therapies, which is currently obstructing patient survival. The unique tumor microenvironment (TME) of mBC in bone offers an array of targets for therapeutic development. The mBC TME in bone presents a predominantly osteolytic or destructive bone pathology, where bone mineral loss is driven by increased resorption of bone by osteoclasts. We discuss therapeutics targeting the mBC cells, bone cells, immune cells, and other stromal cells in the bone TME, including treatments that are currently used in the clinic, under development, and are potential new avenues for therapy. Therapeutic advancements targeting the TME of mBC in bone could be applied to other bone-resident cancers, including myeloma and metastatic prostate cancer bone lesions. These precision oncology approaches to mBC treatment will improve the quality of life and clinical outcomes of patients with mBC bone lesions.

Breast Cancer Endocrine Therapy Promotes Weight Gain With Distinct Adipose Tissue Effects in Lean and Obese Female Mice.

Breast cancer survivors treated with tamoxifen and aromatase inhibitors report weight gain and have an elevated risk of type 2 diabetes, especially if they have obesity. These patient experiences are inconsistent with, preclinical studies using high doses of tamoxifen which reported acute weight loss. We investigated the impact of breast cancer endocrine therapies in a preclinical model of obesity and in a small group of breast adipose tissue samples from women taking tamoxifen to understand the clinical findings. Mature female mice were housed at thermoneutrality and fed either a low-fat/low-sucrose (LFLS) or a high-fat/high-sucrose (HFHS) diet. Consistent with the high expression of Esr1 observed in mesenchymal stem cells from adipose tissue, endocrine therapy was associated with adipose accumulation and more preadipocytes compared with estrogen-treated control mice but resulted in fewer adipocyte progenitors only in the context of HFHS. Analysis of subcutaneous adipose stromal cells revealed diet- and treatment-dependent effects of endocrine therapies on various cell types and genes, illustrating the complexity of adipose tissue estrogen receptor signaling. Breast cancer therapies supported adipocyte hypertrophy and associated with hepatic steatosis, hyperinsulinemia, and glucose intolerance, particularly in obese females. Current tamoxifen use associated with larger breast adipocyte diameter only in women with obesity. Our translational studies suggest that endocrine therapies may disrupt adipocyte progenitors and support adipocyte hypertrophy, potentially leading to ectopic lipid deposition that may be linked to a greater type 2 diabetes risk. Monitoring glucose tolerance and potential interventions that target insulin action should be considered for some women receiving life-saving endocrine therapies for breast cancer.