Autophagy and senescence facilitate the development of antiestrogen resistance in ER positive breast cancer.

Estrogen receptor positive (ER+) breast cancer is the most common breast cancer diagnosed annually in the US with endocrine-based therapy as standard-of-care for this breast cancer subtype. Endocrine therapy includes treatment with antiestrogens, such as selective estrogen receptor modulators (SERMs), selective estrogen receptor downregulators (SERDs), and aromatase inhibitors (AIs). Despite the appreciable remission achievable with these treatments, a substantial cohort of women will experience primary tumor recurrence, subsequent metastasis, and eventual death due to their disease. In these cases, the breast cancer cells have become resistant to endocrine therapy, with endocrine resistance identified as the major obstacle to the medical oncologist and patient. To combat the development of endocrine resistance, the treatment options for ER+, HER2 negative breast cancer now include CDK4/6 inhibitors used as adjuvants to antiestrogen treatment. In addition to the dysregulated activity of CDK4/6, a plethora of genetic and biochemical mechanisms have been identified that contribute to endocrine resistance. These mechanisms, which have been identified by lab-based studies utilizing appropriate cell and animal models of breast cancer, and by clinical studies in which gene expression profiles identify candidate endocrine resistance genes, are the subject of this review. In addition, we will discuss molecular targeting strategies now utilized in conjunction with endocrine therapy to combat the development of resistance or target resistant breast cancer cells. Of approaches currently being explored to improve endocrine treatment efficacy and patient outcome, two adaptive cell survival mechanisms, autophagy, and "reversible" senescence, are considered molecular targets. Autophagy and/or senescence induction have been identified in response to most antiestrogen treatments currently being used for the treatment of ER+ breast cancer and are often induced in response to CDK4/6 inhibitors. Unfortunately, effective strategies to target these cell survival pathways have not yet been successfully developed. Thus, there is an urgent need for the continued interrogation of autophagy and "reversible" senescence in clinically relevant breast cancer models with the long-term goal of identifying new molecular targets for improved treatment of ER+ breast cancer.

Irregular Shaped Small Nodule Detection Using a Robust Scan Statistic.

The spatial scan statistics based on the Poisson and binomial models are the most common methods to detect spatial clusters in disease surveillance. These models rely on Monte-Carlo simulation which are time consuming. Moreover, frequently, datasets present over-dispersion which cannot be handled by them. Thus, we have the following goals. First, we propose irregularly shaped spatial scan for the Bell, Poisson, and binomial. The Bell distribution has just one parameter but it is capable of handling over-dispersed datasets. Second, we apply these scan statistics to big maps. A fast version, without Monte-Carlo simulation, for the proposed Poisson and binomial scans is introduced. Intensive simulation studies are carried out to assess the quality of the proposals. In addition, we show the time improvement of the fast scan versions over their traditional ones. Finally, we end the paper with an application on the detection of irregular shape small nodules in a medical image. Supplementary Information: The online version contains supplementary material available at 10.1007/s12561-022-09353-7.

FGF10: Type III Epithelial Mesenchymal Transition and Invasion in Breast Cancer Cell Lines.

PURPOSE: Fibroblastic growth factor-10 (FGF-10) has an important role in type I epithelial mesenchymal transition (EMT) during the embryonic period of life (gastrulation). Since EMT has a critical role during cancer cells invasion and metastasis (type III) this study sought to investigate the possible role of FGF-10 in type III EMT by monitoring breast cancer cell lines' behavior by FGF-10 regulation. METHODS: MCF-7 and MDA-MB-231 cell lines with different levels of FGF10 expression were treated with FGF-10 recombinant protein and FGF-10 siRNA, respectively. RESULTS: The cell viability, migration, colony formation and wound healing have a direct relationship with FGF-10 expression, while FGF-10 expression decreased apoptosis. All mesenchymal factors (such as vimentin, N cadherin, snail, slug, TGF-ß) increased due to FGF-10 expression with contrary expression of epithelial markers (such as E-cadherin). Moreover, GSK3ß phosphorylation (inactivation) increased with FGF-10 expression. CONCLUSION: The important role of FGF-10 in type III EMT on cancer cells and initiation of metastasis via various kinds of signaling pathways has been suggested.