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Simple Summary: L-type amino acid transporters such as LAT1 and LAT3 are associated with the uptake of essential amino acids. In particular, LAT1 regulates mammalian target of rapamycin complex 1 (mTORC1) signaling and cell proliferation by regulating leucine uptake. The purpose of this study is to clarify amino acid metabolism via LAT1 and LAT3 in breast cancer and the potential roles of LAT1 in the development of therapeutic resistance and clinical outcome of the patients. Results demonstrated that high LAT1 status was associated with tumor progression in breast cancer patients who received neoadjuvant hormone therapy (NAH), and LAT1 expression in the estrogen deprivation-resistant (EDR) breast carcinoma cell lines were upregulated. JPH203, a selective LAT1 inhibitor, demonstrated inhibitory effects on cell proliferation in the EDR cells. Therefore, LAT1 could serve not only as a prognosis biomarker but also a therapeutic target in estrogen receptor (ER)-positive breast cancer patients. The PI3K/Akt/mTOR pathway has been well known to interact with the estrogen receptor (ER)-pathway and to be also frequently upregulated in aromatase inhibitor (AI)-resistant breast cancer patients. Intracellular levels of free amino acids, especially leucine, regulate the mammalian target of rapamycin complex 1 (mTORC1) activation. L-type amino acid transporters such as LAT1 and LAT3 are associated with the uptake of essential amino acids. LAT1 expression could mediate leucine uptake, mTORC1 signaling, and cell proliferation. Therefore, in this study, we explored amino acid metabolism, including LAT1, in breast cancer and clarified the potential roles of LAT1 in the development of therapeutic resistance and the eventual clinical outcome of the patients. We evaluated LAT1 and LAT3 expression before and after neoadjuvant hormone therapy (NAH) and examined LAT1 function and expression in estrogen deprivation-resistant (EDR) breast carcinoma cell lines. Tumors tended to be in advanced stages in the cases whose LAT1 expression was high. LAT1 expression in the EDR cell lines was upregulated. JPH203, a selective LAT1 inhibitor, demonstrated inhibitory effects on cell proliferation in EDR cells. Hormone therapy changed the tumor microenvironment and resulted in metabolic reprogramming through inducing LAT1 expression. LAT1 expression then mediated leucine uptake, enhanced mTORC1 signaling, and eventually resulted in AI resistance. Therefore, LAT1 could be the potential therapeutic target in AI-resistant breast cancer patients. [ABSTRACT FROM AUTHOR]

Background Ductal carcinoma in situ (DCIS) incidence has grown with the implementation of screening and its detection varies across International Cancer Screening Network (ICSN) countries. The aim of this survey is to describe the management of screen-detected DCIS in ICSN countries and to evaluate the potential for treatment related morbidity. Methods We sought screen-detected DCIS data from the ICSN countries identified during 2004–2008. We adopted standardised data collection forms and analysis and explored DCIS diagnosis and treatment processes ranging from pre-operative diagnosis to type of surgery and radiotherapy. Results Twelve countries contributed data from a total of 15 screening programmes, all from Europe except the United States of America and Japan. Among women aged 50–69 years, 7,176,050 screening tests and 5324 screen-detected DCIS were reported. From 21% to 93% of DCIS had a pre-operative diagnosis (PO); 67–90% of DCIS received breast conservation surgery (BCS), and in 41–100% of the cases this was followed by radiotherapy; 6.4–59% received sentinel lymph node biopsy (SLNB) only and 0.8–49% axillary dissection (ALND) with 0.6% (range by programmes 0–8.1%) being node positive. Among BCS patients 35% received SLNB only and 4.8% received ALND. Starting in 2006, PO and SLNB use increased while ALND remained stable. SLNB and ALND were associated with larger size and higher grade DCIS lesions. Conclusions Variation in DCIS management among screened women is wide and includes lymph node surgery beyond what is currently recommended. This indicates the presence of varying levels of overtreatment and the potential for its reduction. [ABSTRACT FROM AUTHOR]

Abstract: Background: There is concern about detection of ductal carcinoma in situ (DCIS) in screening mammography. DCIS accounts for a substantial proportion of screen-detected lesions but its effect on breast cancer mortality is debated. The International Cancer Screening Network conducted a comparative analysis to determine variation in DCIS detection. Patients and Methods: Data were collected during 2004–2008 on number of screening examinations, detected breast cancers, DCIS cases and Globocan 2008 breast cancer incidence rates derived from national or regional cancer registers. We calculated screen-detection rates for breast cancers and DCIS. Results: Data were obtained from 15 screening settings in 12 countries; 7,176,050 screening examinations; 29,605 breast cancers and 5324 DCIS cases. The ratio between highest and lowest breast cancer incidence was 2.88 (95% confidence interval (CI) 2.76–3.00); 2.97 (95% CI 2.51–3.51) for detection of breast cancer; and 3.49 (95% CI 2.70–4.51) for detection of DCIS. Conclusions: Considerable international variation was found in DCIS detection. This variation could not be fully explained by variation in incidence nor in breast cancer detection rates. It suggests the potential for wide discrepancies in management of DCIS resulting in overtreatment of indolent DCIS or undertreatment of potentially curable disease. Comprehensive cancer registration is needed to monitor DCIS detection. Efforts to understand discrepancies and standardise management may improve care. [Copyright &y& Elsevier]