Extracellular vesicles from young women's breast cancer patients drive increased invasion of non-malignant cells via the Focal Adhesion Kinase pathway: a proteomic approach.

BACKGROUND: Extracellular vesicles (EVs) are small membrane particles that contribute to cancer progression and metastases by transporting biologically significant proteins and nucleic acids. They may also serve as biomarkers of various disease states or important therapeutic targets. Breast cancer EVs have the potential to change the behavior of other cells in their microenvironment. However, the proteomic content of EVs isolated from young women's breast cancer patients and the mechanisms underlying the influence of EVs on tumor cell behavior have not yet been reported. METHODS: In our current translational studies, we compared the proteomic content of EVs isolated from invasive breast cancer cell lines and plasma samples from young women's breast cancer (YWBC) patients and age-matched healthy donors using mass spectrometry. We analyzed the functionality of EVs in two dimensional tumor cell invasion assays and the gene expression changes in tumor cells after incubation with EVs. RESULTS: We found that treatment with EVs from both invasive breast cancer cell lines and plasma of YWBC patients altered the invasive properties of non-invasive breast cancer cells. Proteomics identified differences between EVs from YWBC patients and healthy donors that correlated with their altered function. Further, we identified gene expression changes in non-invasive breast cancer cells after treatment with EVs that implicate the Focal Adhesion Kinase (FAK) signaling pathway as a potential targetable pathway affected by breast cancer-derived EVs. CONCLUSIONS: Our results suggest that the proteome of EVs from breast cancer patients reflects their functionality in tumor motility assays and may help elucidate the role of EVs in breast cancer progression.

Metformin inhibits stromal aromatase expression and tumor progression in a rodent model of postmenopausal breast cancer.

BACKGROUND: Obesity and type II diabetes are linked to increased breast cancer risk in postmenopausal women. Patients treated with the antidiabetic drug metformin for diabetes or metabolic syndrome have reduced breast cancer risk, a greater pathologic complete response to neoadjuvant therapy, and improved breast cancer survival. We hypothesized that metformin may be especially effective when targeted to the menopausal transition, as this is a lifecycle window when weight gain and metabolic syndrome increase, and is also when the risk for obesity-related breast cancer increases. METHODS: Here, we used an 1-methyl-1-nitrosourea (MNU)-induced mammary tumor rat model of estrogen receptor (ER)-positive postmenopausal breast cancer to evaluate the long-term effects of metformin administration on metabolic and tumor endpoints. In this model, ovariectomy (OVX) induces rapid weight gain, and an impaired whole-body response to excess calories contributes to increased tumor glucose uptake and increased tumor proliferation. Metformin treatment was initiated in tumor-bearing animals immediately prior to OVX and maintained for the duration of the study. RESULTS: Metformin decreased the size of existing mammary tumors and inhibited new tumor formation without changing body weight or adiposity. Decreased lipid accumulation in the livers of metformin-treated animals supports the ability of metformin to improve overall metabolic health. We also found a decrease in the number of aromatase-positive, CD68-positive macrophages within the tumor microenvironment, suggesting that metformin targets the immune microenvironment in addition to improving whole-body metabolism. CONCLUSIONS: These findings suggest that peri-menopause/menopause represents a unique window of time during which metformin may be highly effective in women with established, or at high risk for developing, breast cancer.

Association Between Postpartum Breast Cancer Diagnosis and Metastasis and the Clinical Features Underlying Risk.

Importance: In women 45 years or younger, breast cancer diagnosis after childbirth increases the risk for metastasis and death, yet limited data exist to define this window of risk and associated prognostic factors. Objective: To assess the window of elevated risk for metastasis following a postpartum breast cancer (PPBC) diagnosis and whether clinical prognostic factors are associated with the increased risk. Design, Setting, and Participants: This multicenter cohort study conducted using cases from the Colorado Young Women's Breast Cancer Cohort diagnosed between January 1, 1981, and December 31, 2014, included 701 women 45 years or younger with stage I to III invasive breast cancer for whom parity data, including time of last childbirth, were available. Data analysis was conducted from July 1 to September 30, 2017. This study involved a tertiary care academic hospital-based breast center and its regional affiliates with cases from the greater Rocky Mountain region. Exposures: Primary exposures were prior childbirth or no childbirth, time between most recent childbirth and breast cancer diagnosis, and time between breast cancer diagnosis and metastasis. Main Outcomes and Measures: The primary outcome was distant metastasis-free survival. Results: A total of 701 women 45 years or younger from the greater Rocky Mountain states region were included in the analysis; mean (SD) age at diagnosis was 37.9 (5.1) years. Breast cancer diagnosis within 10 years after parturition was associated with elevated risk for metastasis, particularly in women with stage I or II disease. In addition, women with PPBC diagnosed within 10 years of a completed pregnancy that was estrogen receptor-positive showed distant metastasis-free survival similar to that of nulliparous patients with estrogen receptor-negative cancer, and women with estrogen receptor-negative PPBC had further reduced metastasis-free survival. Moreover, women with PPBC had increased lymphovascular invasion and lymph node involvement. In addition, tumor-associated Ki67 positivity identified 129 patients with luminal B cancer in the cohort that, independent of parity status, had poorer prognosis compared with patients with luminal A cancer, although it did not reach statistical significance. Conclusions and Relevance: Diagnosis of PPBC within 10 years post partum appears to be associated with an increased risk for metastasis. This increased risk was highest in stages I and II cancer at diagnosis and present in both patients with estrogen receptor-positive and estrogen receptor-negative cancer, persisting in estrogen receptor-positive cases for up to 15 years after diagnosis. Postpartum breast cancer diagnoses were not associated with increased Ki67 index but were associated with increased lymphovascular invasion and lymph node involvement compared with breast cancer in nulliparous patients.

Overcoming Therapeutic Resistance of Triple Positive Breast Cancer with CDK4/6 Inhibition.

Triple positive breast cancers overexpress both the human epidermal growth factor receptor 2 (HER2) oncogene and the hormonal receptors (HR) to estrogen and progesterone. These cancers represent a unique therapeutic challenge because of a bidirectional cross-talk between the estrogen receptor alpha (ERα) and HER2 pathways leading to tumor progression and resistance to targeted therapy. Attempts to combine standard of care HER2-targeted drugs with antihormonal agents for the treatment of HR+/HER2+ breast cancer yielded encouraging results in preclinical experiments but did improve overall survival in clinical trial. In this review, we dissect multiple mechanisms of therapeutic resistance typical of HR+/HER2+ breast cancer, summarize prior clinical trials of targeted agents, and describe novel rational drug combinations that include antihormonal agents, HER2-targeted drugs, and CDK4/6 inhibitors for treatment of the HR+/HER2+ breast cancer subtype.